Abstract
Mesenchymal stem cells (MSCs) are isolated from multiple biological tissues—adult bone marrow and adipose tissues and neonatal tissues such as umbilical cord and placenta. In vitro, MSCs show biological features of extensive proliferation ability and multipotency. Moreover, MSCs have trophic, homing/migration and immunosuppression functions that have been demonstrated both in vitro and in vivo. A number of clinical trials are using MSCs for therapeutic interventions in severe degenerative and/or inflammatory diseases, including Crohn’s disease and graft-versus-host disease, alone or in combination with other drugs. MSCs are promising for therapeutic applications given the ease in obtaining them, their genetic stability, their poor immunogenicity and their curative properties for tissue repair and immunomodulation. The success of MSC therapy in degenerative and/or inflammatory diseases might depend on the robustness of the biological functions of MSCs, which should be linked to their therapeutic potency. Here, we outline the fundamental and advanced concepts of MSC biological features and underline the biological functions of MSCs in their basic and translational aspects in therapy for degenerative and/or inflammatory diseases.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Squillaro T, Peluso G, Galderisi U (2016) Clinical trials with mesenchymal stem cells: an update. Cell Transplant 25:829–848. https://doi.org/10.3727/096368915X689622
Galipeau J, Sensebe L (2018) Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell 22:824–833. https://doi.org/10.1016/j.stem.2018.05.004
Trounson A, McDonald C (2015) Stem cell therapies in clinical trials: progress and challenges. Cell Stem Cell 17:11–22. https://doi.org/10.1016/j.stem.2015.06.007
Naji A et al (2013) Concise review: combining human leukocyte antigen G and mesenchymal stem cells for immunosuppressant biotherapy. Stem Cells 31:2296–2303. https://doi.org/10.1002/stem.1494
Wei X et al (2013) Mesenchymal stem cells: a new trend for cell therapy. Acta Pharmacol Sin 34:747–754. https://doi.org/10.1038/aps.2013.50
Naji A et al (2017) Rationale for determining the functional potency of mesenchymal stem cells in preventing regulated cell death for therapeutic use. Stem Cells Transl Med 6:713–719. https://doi.org/10.5966/sctm.2016-0289
Chinnadurai R et al (2016) Cryopreserved mesenchymal stromal cells are susceptible to T-cell mediated apoptosis which is partly rescued by IFNgamma licensing. Stem Cells 34:2429–2442. https://doi.org/10.1002/stem.2415
Galipeau J (2013) The mesenchymal stromal cells dilemma: does a negative phase III trial of random donor mesenchymal stromal cells in steroid-resistant graft-versus-host disease represent a death knell or a bump in the road? Cytotherapy 15:2–8. https://doi.org/10.1016/j.jcyt.2012.10.002
Galipeau J, Krampera M (2015) The challenge of defining mesenchymal stromal cell potency assays and their potential use as release criteria. Cytotherapy 17:125–127. https://doi.org/10.1016/j.jcyt.2014.12.008
Galipeau J et al (2016) International Society for Cellular Therapy perspective on immune functional assays for mesenchymal stromal cells as potency release criterion for advanced phase clinical trials. Cytotherapy 18:151–159. https://doi.org/10.1016/j.jcyt.2015.11.008
Phinney DG et al (2013) MSCs: science and trials. Nat Med 19:812. https://doi.org/10.1038/nm.3220
Sheridan C (2018) First off-the-shelf mesenchymal stem cell therapy nears European approval. Nat Biotechnol 36:212–214. https://doi.org/10.1038/nbt0318-212a
Bianco P, Robey PG, Simmons PJ (2008) Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2:313–319. https://doi.org/10.1016/j.stem.2008.03.002
Ma S et al (2014) Immunobiology of mesenchymal stem cells. Cell Death Differ 21:216–225. https://doi.org/10.1038/cdd.2013.158
Nombela-Arrieta C, Ritz J, Silberstein LE (2011) The elusive nature and function of mesenchymal stem cells. Nat Rev Mol Cell Biol 12:126–131. https://doi.org/10.1038/nrm3049
Sacchetti B et al (2016) No identical “mesenchymal stem cells” at different times and sites: human committed progenitors of distinct origin and differentiation potential are incorporated as adventitial cells in microvessels. Stem Cell Rep 6:897–913. https://doi.org/10.1016/j.stemcr.2016.05.011
Spees JL, Lee RH, Gregory CA (2016) Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res Ther 7:125. https://doi.org/10.1186/s13287-016-0363-7
Friedenstein AJ, Chailakhjan RK, Lalykina KS (1970) The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 3:393–403
Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV (1974) Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation 17:331–340
Friedenstein AJ et al (1974) Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol 2:83–92
Friedenstein AJ, Gorskaja JF, Kulagina NN (1976) Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol 4:267–274
Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP (1968) Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation 6:230–247
Friedenstein AJ, Piatetzky S II, Petrakova KV (1966) Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol 16:381–390
Castro-Malaspina H et al (1980) Characterization of human bone marrow fibroblast colony-forming cells (CFU-F) and their progeny. Blood 56:289–301
Jinnai I, Bessho M, Murohashi I, Nara N, Hirashima K (1984) Relationship between fibroblastoid colony-forming units (CFU-f) and hemopoietic precursor cells in normal human bone marrow. Int J Cell Cloning 2:341–347. https://doi.org/10.1002/stem.5530020602
Nara N, Jinnai I, Imai Y, Bessho M, Hirashima K (1984) Reduction of granulocyte-macrophage progenitor cells (CFU-C) and fibroblastoid colony-forming units (CFU-F) by leukemic cells in human and murine leukemia. Acta Haematol 72:171–180. https://doi.org/10.1159/000206383
Dennis JE, Haynesworth SE, Young RG, Caplan AI (1992) Osteogenesis in marrow-derived mesenchymal cell porous ceramic composites transplanted subcutaneously: effect of fibronectin and laminin on cell retention and rate of osteogenic expression. Cell Transplant 1:23–32
Owen M (1988) Marrow stromal stem cells. J Cell Sci Suppl 10:63–76
Owen M, Friedenstein AJ (1988) Stromal stem cells: marrow-derived osteogenic precursors. Ciba Found Symp 136:42–60
Chang J, Allen TD, Dexter TM (1989) Long-term bone marrow cultures: their use in autologous marrow transplantation. Cancer Cells 1:17–24
Dexter TM (1982) Stromal cell associated haemopoiesis. J Cell Physiol Suppl 1:87–94
Dexter TM, Spooncer E (1987) Growth and differentiation in the hemopoietic system. Annu Rev Cell Biol 3:423–441. https://doi.org/10.1146/annurev.cb.03.110187.002231
Dexter TM, Whetton AD, Spooncer E, Heyworth C, Simmons P (1985) The role of stromal cells and growth factors in haemopoiesis and modulation of their effects by the src oncogene. J Cell Sci Suppl 3:83–95
Beresford JN (1989) Osteogenic stem cells and the stromal system of bone and marrow. Clin Orthop Relat Res 240:270–280
Castro-Malaspina H et al (1982) Characteristics of bone marrow fibroblast colony-forming cells (CFU-F) and their progeny in patients with myeloproliferative disorders. Blood 59:1046–1054
Castro-Malaspina H, Ebell W, Wang S (1984) Human bone marrow fibroblast colony-forming units (CFU-F). Prog Clin Biol Res 154:209–236
Haynesworth SE, Baber MA, Caplan AI (1992) Cell surface antigens on human marrow-derived mesenchymal cells are detected by monoclonal antibodies. Bone 13:69–80
Haynesworth SE, Baber MA, Caplan AI (1996) Cytokine expression by human marrow-derived mesenchymal progenitor cells in vitro: effects of dexamethasone and IL-1 alpha. J Cell Physiol 166:585–592. https://doi.org/10.1002/(SICI)1097-4652(199603)166:3%3c585:AID-JCP13%3e3.0.CO;2-6
Haynesworth SE, Goshima J, Goldberg VM, Caplan AI (1992) Characterization of cells with osteogenic potential from human marrow. Bone 13:81–88
Jaiswal N, Haynesworth SE, Caplan AI, Bruder SP (1997) Osteogenic differentiation of purified, culture-expanded human mesenchymal stem cells in vitro. J Cell Biochem 64:295–312
Vilamitjana-Amedee J, Bareille R, Rouais F, Caplan AI, Harmand MF (1993) Human bone marrow stromal cells express an osteoblastic phenotype in culture. Vitro Cell Dev Biol Anim 29A:699–707
Caplan AI (1991) Mesenchymal stem cells. J Orthop Res 9:641–650. https://doi.org/10.1002/jor.1100090504
Bruder SP, Fink DJ, Caplan AI (1994) Mesenchymal stem cells in bone development, bone repair, and skeletal regeneration therapy. J Cell Biochem 56:283–294. https://doi.org/10.1002/jcb.240560303
Bianco P (2014) “Mesenchymal” stem cells. Annu Rev Cell Dev Biol 30:677–704. https://doi.org/10.1146/annurev-cellbio-100913-013132
Caplan AI (2017) Mesenchymal stem cells: time to change the name! Stem Cells Transl Med 6:1445–1451. https://doi.org/10.1002/sctm.17-0051
Bhartiya D (2018) The need to revisit the definition of mesenchymal and adult stem cells based on their functional attributes. Stem Cell Res Ther 9:78. https://doi.org/10.1186/s13287-018-0833-1
Caplan AI, Dennis JE (2006) Mesenchymal stem cells as trophic mediators. J Cell Biochem 98:1076–1084. https://doi.org/10.1002/jcb.20886
Lazarus HM, Haynesworth SE, Gerson SL, Rosenthal NS, Caplan AI (1995) Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant 16:557–564
Horwitz EM et al (2005) Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy 7:393–395. https://doi.org/10.1080/14653240500319234
Charbord P (2010) Bone marrow mesenchymal stem cells: historical overview and concepts. Hum Gene Ther 21:1045–1056. https://doi.org/10.1089/hum.2010.115
Delorme B, Chateauvieux S, Charbord P (2006) The concept of mesenchymal stem cells. Regen Med 1:497–509. https://doi.org/10.2217/17460751.1.4.497
Phinney DG, Sensebe L (2013) Mesenchymal stromal cells: misconceptions and evolving concepts. Cytotherapy 15:140–145. https://doi.org/10.1016/j.jcyt.2012.11.005
Bhakta S, Hong P, Koc O (2006) The surface adhesion molecule CXCR53 stimulates mesenchymal stem cell migration to stromal cell-derived factor-1 in vitro but does not decrease apoptosis under serum deprivation. Cardiovasc Revasc Med 7:19–24. https://doi.org/10.1016/j.carrev.2005.10.008
Chamberlain G, Fox J, Ashton B, Middleton J (2007) Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 25:2739–2749. https://doi.org/10.1634/stemcells.2007-0197
Cheng Z et al (2008) Targeted migration of mesenchymal stem cells modified with CXCR55 gene to infarcted myocardium improves cardiac performance. Mol Ther 16:571–579. https://doi.org/10.1038/sj.mt.6300374
De Becker A et al (2007) Migration of culture-expanded human mesenchymal stem cells through bone marrow endothelium is regulated by matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-3. Haematologica 92:440–449
Henschler R, Deak E, Seifried E (2008) Homing of mesenchymal stem cells. Transfus Med Hemother 35:306–312. https://doi.org/10.1159/000143110
Ji JF, He BP, Dheen ST, Tay SS (2004) Interactions of chemokines and chemokine receptors mediate the migration of mesenchymal stem cells to the impaired site in the brain after hypoglossal nerve injury. Stem Cells 22:415–427. https://doi.org/10.1634/stemcells.22-3-415
Sackstein R et al (2008) Ex vivo glycan engineering of CD44 programs human multipotent mesenchymal stromal cell trafficking to bone. Nat Med 14:181–187. https://doi.org/10.1038/nm1703
Son BR et al (2006) Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR60 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells 24:1254–1264. https://doi.org/10.1634/stemcells.2005-0271
Sordi V et al (2005) Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood 106:419–427. https://doi.org/10.1182/blood-2004-09-3507
Wu GD et al (2003) Migration of mesenchymal stem cells to heart allografts during chronic rejection. Transplantation 75:679–685. https://doi.org/10.1097/01.TP.0000048488.35010.95
Devine SM, Peter S, Martin BJ, Barry F, McIntosh KR (2001) Mesenchymal stem cells: stealth and suppression. Cancer J 7(Suppl 2):S76–S82
Djouad F et al (2003) Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals. Blood 102:3837–3844. https://doi.org/10.1182/blood-2003-04-1193
Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105:1815–1822. https://doi.org/10.1182/blood-2004-04-1559
Le Blanc K (2003) Immunomodulatory effects of fetal and adult mesenchymal stem cells. Cytotherapy 5:485–489. https://doi.org/10.1080/14653240310003611
Maitra B et al (2004) Human mesenchymal stem cells support unrelated donor hematopoietic stem cells and suppress T-cell activation. Bone Marrow Transplant 33:597–604. https://doi.org/10.1038/sj.bmt.1704400
Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC (2003) Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation 75:389–397. https://doi.org/10.1097/01.TP.0000045055.63901.A9
Caplan AI (2009) Why are MSCs therapeutic? New data: new insight. J Pathol 217:318–324. https://doi.org/10.1002/path.2469
Hass R, Kasper C, Bohm S, Jacobs R (2011) Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal 9:12. https://doi.org/10.1186/1478-811X-9-12
Kolf CM, Cho E, Tuan RS (2007) Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation. Arthritis Res Ther 9:204. https://doi.org/10.1186/ar2116
Maria AT et al (2017) Adipose-derived mesenchymal stem cells in autoimmune disorders: state of the art and perspectives for systemic sclerosis. Clin Rev Allergy Immunol 52:234–259. https://doi.org/10.1007/s12016-016-8552-9
Pittenger MF et al (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147
Beyer Nardi N, da Silva Meirelles L (2006) Mesenchymal stem cells: isolation, in vitro expansion and characterization. Handb Exp Pharmacol 174:249–282. https://doi.org/10.1007/978-3-540-77855-4_11
da Silva Meirelles L, Chagastelles PC, Nardi NB (2006) Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 119:2204–2213. https://doi.org/10.1242/jcs.02932
Gronthos S et al (2003) Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow. J Cell Sci 116:1827–1835
Shi S, Gronthos S (2003) Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J Bone Miner Res 18:696–704. https://doi.org/10.1359/jbmr.2003.18.4.696
Gronthos S, Zannettino AC (2008) A method to isolate and purify human bone marrow stromal stem cells. Methods Mol Biol 449:45–57. https://doi.org/10.1007/978-1-60327-169-1_3
Zannettino AC et al (2008) Multipotential human adipose-derived stromal stem cells exhibit a perivascular phenotype in vitro and in vivo. J Cell Physiol 214:413–421. https://doi.org/10.1002/jcp.21210
Kern S, Eichler H, Stoeve J, Kluter H, Bieback K (2006) Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 24:1294–1301. https://doi.org/10.1634/stemcells.2005-0342
Lee RH et al (2004) Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol Biochem 14:311–324. https://doi.org/10.1159/000080341
Zuk PA et al (2002) Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13:4279–4295. https://doi.org/10.1091/mbc.e02-02-0105
Yin JQ, Zhu J, Ankrum JA (2019) Manufacturing of primed mesenchymal stromal cells for therapy. Nat Biomed Eng 3:90–104. https://doi.org/10.1038/s41551-018-0325-8
Wang LT et al (2016) Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials. J Biomed Sci 23:76. https://doi.org/10.1186/s12929-016-0289-5
Lee HS et al (2003) Multipotential mesenchymal stem cells from femoral bone marrow near the site of osteonecrosis. Stem Cells 21:190–199. https://doi.org/10.1634/stemcells.21-2-190
Wagey R, Short B (2013) Isolation, enumeration, and expansion of human mesenchymal stem cells in culture. Methods Mol Biol 946:315–334. https://doi.org/10.1007/978-1-62703-128-8_20
Sensebe L (2008) Clinical grade production of mesenchymal stem cells. Biomed Mater Eng 18:S3–S10
Varghese J, Griffin M, Mosahebi A, Butler P (2017) Systematic review of patient factors affecting adipose stem cell viability and function: implications for regenerative therapy. Stem Cell Res Ther 8:45. https://doi.org/10.1186/s13287-017-0483-8
Zuk PA et al (2001) Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7:211–228. https://doi.org/10.1089/107632701300062859
Nagamura-Inoue T, He H (2014) Umbilical cord-derived mesenchymal stem cells: their advantages and potential clinical utility. World J Stem Cells 6:195–202. https://doi.org/10.4252/wjsc.v6.i2.195
Bieback K, Brinkmann I (2010) Mesenchymal stromal cells from human perinatal tissues: from biology to cell therapy. World J Stem Cells 2:81–92. https://doi.org/10.4252/wjsc.v2.i4.81
Scheller EL, Cawthorn WP, Burr AA, Horowitz MC, MacDougald OA (2016) Marrow adipose tissue: trimming the fat. Trends Endocrinol Metab 27:392–403. https://doi.org/10.1016/j.tem.2016.03.016
Corselli M, Chen CW, Crisan M, Lazzari L, Peault B (2010) Perivascular ancestors of adult multipotent stem cells. Arterioscler Thromb Vasc Biol 30:1104–1109. https://doi.org/10.1161/ATVBAHA.109.191643
Song N, Armstrong AD, Li F, Ouyang H, Niyibizi C (2014) Multipotent mesenchymal stem cells from human subacromial bursa: potential for cell based tendon tissue engineering. Tissue Eng Part A 20:239–249. https://doi.org/10.1089/ten.TEA.2013.0197
Vaculik C et al (2012) Human dermis harbors distinct mesenchymal stromal cell subsets. J Invest Dermatol 132:563–574. https://doi.org/10.1038/jid.2011.355
Fournier BP et al (2010) Multipotent progenitor cells in gingival connective tissue. Tissue Eng Part A 16:2891–2899. https://doi.org/10.1089/ten.TEA.2009.0796
Cheng MT, Yang HW, Chen TH, Lee OK (2009) Isolation and characterization of multipotent stem cells from human cruciate ligaments. Cell Prolif 42:448–460. https://doi.org/10.1111/j.1365-2184.2009.00611.x
Chong PP, Selvaratnam L, Abbas AA, Kamarul T (2012) Human peripheral blood derived mesenchymal stem cells demonstrate similar characteristics and chondrogenic differentiation potential to bone marrow derived mesenchymal stem cells. J Orthop Res 30:634–642. https://doi.org/10.1002/jor.21556
Fan J, Varshney RR, Ren L, Cai D, Wang DA (2009) Synovium-derived mesenchymal stem cells: a new cell source for musculoskeletal regeneration. Tissue Eng Part B Rev 15:75–86. https://doi.org/10.1089/ten.teb.2008.0586
Miao Z et al (2006) Isolation of mesenchymal stem cells from human placenta: comparison with human bone marrow mesenchymal stem cells. Cell Biol Int 30:681–687. https://doi.org/10.1016/j.cellbi.2006.03.009
Wang LT et al (2018) Differentiation of mesenchymal stem cells from human induced pluripotent stem cells results in downregulation of c-Myc and DNA replication pathways with immunomodulation toward CD4 and CD8 cells. Stem Cells 36:903–914. https://doi.org/10.1002/stem.2795
Lennon DP, Haynesworth SE, Bruder SP, Jaiswal N, Caplan AI (1996) Human and animal mesenchymal progenitor cells from bone marrow: identification of serum for optimal selection and proliferation. Vitro Cell Dev Biol Anim 32:602–611
Rojewski MT et al (2013) GMP-compliant isolation and expansion of bone marrow-derived MSCs in the closed, automated device quantum cell expansion system. Cell Transplant 22:1981–2000. https://doi.org/10.3727/096368912X657990
Corotchi MC et al (2013) Isolation method and xeno-free culture conditions influence multipotent differentiation capacity of human Wharton’s jelly-derived mesenchymal stem cells. Stem Cell Res Ther 4:81. https://doi.org/10.1186/scrt232
Dos Santos F et al (2014) A xenogeneic-free bioreactor system for the clinical-scale expansion of human mesenchymal stem/stromal cells. Biotechnol Bioeng 111:1116–1127. https://doi.org/10.1002/bit.25187
Sensebe L, Gadelorge M, Fleury-Cappellesso S (2013) Production of mesenchymal stromal/stem cells according to good manufacturing practices: a review. Stem Cell Res Ther 4:66. https://doi.org/10.1186/scrt217
Dos Santos F et al (2010) Ex vivo expansion of human mesenchymal stem cells: a more effective cell proliferation kinetics and metabolism under hypoxia. J Cell Physiol 223:27–35. https://doi.org/10.1002/jcp.21987
Fotia C, Massa A, Boriani F, Baldini N, Granchi D (2015) Hypoxia enhances proliferation and stemness of human adipose-derived mesenchymal stem cells. Cytotechnology 67:1073–1084. https://doi.org/10.1007/s10616-014-9731-2
Eaker S et al (2013) Concise review: guidance in developing commercializable autologous/patient-specific cell therapy manufacturing. Stem Cells Transl Med 2:871–883. https://doi.org/10.5966/sctm.2013-0050
Blazquez-Prunera A, Almeida CR, Barbosa MA (2017) Human bone marrow mesenchymal stem/stromal cells preserve their immunomodulatory and chemotactic properties when expanded in a human plasma derived xeno-free medium. Stem Cells Int 2017:2185351. https://doi.org/10.1155/2017/2185351
Blazquez-Prunera A, Diez JM, Gajardo R, Grancha S (2017) Human mesenchymal stem cells maintain their phenotype, multipotentiality, and genetic stability when cultured using a defined xeno-free human plasma fraction. Stem Cell Res Ther 8:103. https://doi.org/10.1186/s13287-017-0552-z
Rafiq QA, Brosnan KM, Coopman K, Nienow AW, Hewitt CJ (2013) Culture of human mesenchymal stem cells on microcarriers in a 5 l stirred-tank bioreactor. Biotechnol Lett 35:1233–1245. https://doi.org/10.1007/s10529-013-1211-9
Marquez-Curtis LA, Janowska-Wieczorek A, McGann LE, Elliott JA (2015) Mesenchymal stromal cells derived from various tissues: biological, clinical and cryopreservation aspects. Cryobiology 71:181–197. https://doi.org/10.1016/j.cryobiol.2015.07.003
Moll G et al (2014) Do cryopreserved mesenchymal stromal cells display impaired immunomodulatory and therapeutic properties? Stem Cells 32:2430–2442. https://doi.org/10.1002/stem.1729
Lechanteur C et al (2016) Clinical-scale expansion of mesenchymal stromal cells: a large banking experience. J Transl Med 14:145. https://doi.org/10.1186/s12967-016-0892-y
Wagner W et al (2006) The heterogeneity of human mesenchymal stem cell preparations—evidence from simultaneous analysis of proteomes and transcriptomes. Exp Hematol 34:536–548. https://doi.org/10.1016/j.exphem.2006.01.002
Pevsner-Fischer M, Levin S, Zipori D (2011) The origins of mesenchymal stromal cell heterogeneity. Stem Cell Rev 7:560–568. https://doi.org/10.1007/s12015-011-9229-7
Han ZC, Du WJ, Han ZB, Liang L (2017) New insights into the heterogeneity and functional diversity of human mesenchymal stem cells. Biomed Mater Eng 28:S29–S45. https://doi.org/10.3233/BME-171622
Phinney DG (2012) Functional heterogeneity of mesenchymal stem cells: implications for cell therapy. J Cell Biochem 113:2806–2812. https://doi.org/10.1002/jcb.24166
Mindaye ST, Lo Surdo J, Bauer SR, Alterman MA (2015) The proteomic dataset for bone marrow derived human mesenchymal stromal cells: effect of in vitro passaging. Data Brief 5:864–870. https://doi.org/10.1016/j.dib.2015.10.020
Mindaye ST, Ra M, Lo Surdo J, Bauer SR, Alterman MA (2013) Improved proteomic profiling of the cell surface of culture-expanded human bone marrow multipotent stromal cells. J Proteomics 78:1–14. https://doi.org/10.1016/j.jprot.2012.10.028
Mindaye ST, Ra M, Lo Surdo JL, Bauer SR, Alterman MA (2013) Global proteomic signature of undifferentiated human bone marrow stromal cells: evidence for donor-to-donor proteome heterogeneity. Stem Cell Res 11:793–805. https://doi.org/10.1016/j.scr.2013.05.006
Mindaye ST, Surdo JL, Bauer SR, Alterman MA (2015) System-wide survey of proteomic responses of human bone marrow stromal cells (hBMSCs) to in vitro cultivation. Stem Cell Res 15:655–664. https://doi.org/10.1016/j.scr.2015.09.013
Dominici M et al (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317. https://doi.org/10.1080/14653240600855905
Samsonraj RM et al (2015) Establishing criteria for human mesenchymal stem cell potency. Stem Cells 33:1878–1891. https://doi.org/10.1002/stem.1982
Lv FJ, Tuan RS, Cheung KM, Leung VY (2014) Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells 32:1408–1419. https://doi.org/10.1002/stem.1681
Rennerfeldt DA, Van Vliet KJ (2016) Concise review: when colonies are not clones: evidence and implications of intracolony heterogeneity in mesenchymal stem cells. Stem Cells 34:1135–1141. https://doi.org/10.1002/stem.2296
Cai J, Weiss ML, Rao MS (2004) In search of “stemness”. Exp Hematol 32:585–598. https://doi.org/10.1016/j.exphem.2004.03.013
De Boer J, Wang HJ, Van Blitterswijk C (2004) Effects of Wnt signaling on proliferation and differentiation of human mesenchymal stem cells. Tissue Eng 10:393–401. https://doi.org/10.1089/107632704323061753
Fehrer C et al (2007) Reduced oxygen tension attenuates differentiation capacity of human mesenchymal stem cells and prolongs their lifespan. Aging Cell 6:745–757. https://doi.org/10.1111/j.1474-9726.2007.00336.x
Estrada JC et al (2012) Culture of human mesenchymal stem cells at low oxygen tension improves growth and genetic stability by activating glycolysis. Cell Death Differ 19:743–755. https://doi.org/10.1038/cdd.2011.172
Zimmermann S et al (2003) Lack of telomerase activity in human mesenchymal stem cells. Leukemia 17:1146–1149. https://doi.org/10.1038/sj.leu.2402962
Bernardo ME et al (2007) Human bone marrow derived mesenchymal stem cells do not undergo transformation after long-term in vitro culture and do not exhibit telomere maintenance mechanisms. Cancer Res 67:9142–9149. https://doi.org/10.1158/0008-5472.CAN-06-4690
Wagner W et al (2008) Replicative senescence of mesenchymal stem cells: a continuous and organized process. PLoS One 3:e2213. https://doi.org/10.1371/journal.pone.0002213
Bork S et al (2010) DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells. Aging Cell 9:54–63. https://doi.org/10.1111/j.1474-9726.2009.00535.x
Turinetto V, Vitale E, Giachino C (2016) Senescence in human mesenchymal stem cells: functional changes and implications in stem cell-based therapy. Int J Mol Sci 17:1164. https://doi.org/10.3390/ijms17071164
Jaiswal RK et al (2000) Adult human mesenchymal stem cell differentiation to the osteogenic or adipogenic lineage is regulated by mitogen-activated protein kinase. J Biol Chem 275:9645–9652
Li WJ, Tuli R, Huang X, Laquerriere P, Tuan RS (2005) Multilineage differentiation of human mesenchymal stem cells in a three-dimensional nanofibrous scaffold. Biomaterials 26:5158–5166. https://doi.org/10.1016/j.biomaterials.2005.01.002
Chen Q et al (2016) Fate decision of mesenchymal stem cells: adipocytes or osteoblasts? Cell Death Differ 23:1128–1139. https://doi.org/10.1038/cdd.2015.168
Cristancho AG, Lazar MA (2011) Forming functional fat: a growing understanding of adipocyte differentiation. Nat Rev Mol Cell Biol 12:722–734. https://doi.org/10.1038/nrm3198
Pelttari K, Steck E, Richter W (2008) The use of mesenchymal stem cells for chondrogenesis. Injury 39(Suppl 1):S58–S65. https://doi.org/10.1016/j.injury.2008.01.038
Tuli R et al (2003) Transforming growth factor-beta-mediated chondrogenesis of human mesenchymal progenitor cells involves N-cadherin and mitogen-activated protein kinase and Wnt signaling cross-talk. J Biol Chem 278:41227–41236. https://doi.org/10.1074/jbc.M305312200
Chiou M, Xu Y, Longaker MT (2006) Mitogenic and chondrogenic effects of fibroblast growth factor-2 in adipose-derived mesenchymal cells. Biochem Biophys Res Commun 343:644–652. https://doi.org/10.1016/j.bbrc.2006.02.171
Longobardi L et al (2006) Effect of IGF-I in the chondrogenesis of bone marrow mesenchymal stem cells in the presence or absence of TGF-beta signaling. J Bone Miner Res 21:626–636. https://doi.org/10.1359/jbmr.051213
Schmitt B et al (2003) BMP2 initiates chondrogenic lineage development of adult human mesenchymal stem cells in high-density culture. Differentiation 71:567–577. https://doi.org/10.1111/j.1432-0436.2003.07109003.x
Leung VY et al (2011) SOX9 governs differentiation stage-specific gene expression in growth plate chondrocytes via direct concomitant transactivation and repression. PLoS Genet 7:e1002356. https://doi.org/10.1371/journal.pgen.1002356
Furumatsu T, Tsuda M, Taniguchi N, Tajima Y, Asahara H (2005) Smad3 induces chondrogenesis through the activation of SOX9 via CREB-binding protein/p300 recruitment. J Biol Chem 280:8343–8350. https://doi.org/10.1074/jbc.M413913200
Indrawattana N et al (2004) Growth factor combination for chondrogenic induction from human mesenchymal stem cell. Biochem Biophys Res Commun 320:914–919. https://doi.org/10.1016/j.bbrc.2004.06.029
Friedman MS, Long MW, Hankenson KD (2006) Osteogenic differentiation of human mesenchymal stem cells is regulated by bone morphogenetic protein-6. J Cell Biochem 98:538–554. https://doi.org/10.1002/jcb.20719
Marupanthorn K, Tantrawatpan C, Kheolamai P, Tantikanlayaporn D, Manochantr S (2017) Bone morphogenetic protein-2 enhances the osteogenic differentiation capacity of mesenchymal stromal cells derived from human bone marrow and umbilical cord. Int J Mol Med 39:654–662. https://doi.org/10.3892/ijmm.2017.2872
Sekiya I, Larson BL, Vuoristo JT, Reger RL, Prockop DJ (2005) Comparison of effect of BMP-2, -4, and -6 on in vitro cartilage formation of human adult stem cells from bone marrow stroma. Cell Tissue Res 320:269–276. https://doi.org/10.1007/s00441-004-1075-3
Celil AB, Campbell PG (2005) BMP-2 and insulin-like growth factor-I mediate Osterix (Osx) expression in human mesenchymal stem cells via the MAPK and protein kinase D signaling pathways. J Biol Chem 280:31353–31359
Nakashima K et al (2002) The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 108:17–29
Nishio Y et al (2006) Runx2-mediated regulation of the zinc finger Osterix/Sp7 gene. Gene 372:62–70
Lin GL, Hankenson KD (2011) Integration of BMP, Wnt, and notch signaling pathways in osteoblast differentiation. J Cell Biochem 112:3491–3501
Fontaine C, Cousin W, Plaisant M, Dani C, Peraldi P (2008) Hedgehog signaling alters adipocyte maturation of human mesenchymal stem cells. Stem Cells 26:1037–1046. https://doi.org/10.1634/stemcells.2007-0974
Oldershaw RA et al (2008) Notch signaling through Jagged-1 is necessary to initiate chondrogenesis in human bone marrow stromal cells but must be switched off to complete chondrogenesis. Stem Cells 26:666–674. https://doi.org/10.1634/stemcells.2007-0806
Janeczek Portalska K et al (2012) Endothelial differentiation of mesenchymal stromal cells. PLoS One 7:e46842. https://doi.org/10.1371/journal.pone.0046842
Ullah I, Subbarao RB, Rho GJ (2015) Human mesenchymal stem cells—current trends and future prospective. Biosci Rep 35:e00191. https://doi.org/10.1042/bsr20150025
Beier JP et al (2011) Myogenic differentiation of mesenchymal stem cells co-cultured with primary myoblasts. Cell Biol Int 35:397–406. https://doi.org/10.1042/CBI20100417
Song L, Tuan RS (2004) Transdifferentiation potential of human mesenchymal stem cells derived from bone marrow. FASEB J 18:980–982. https://doi.org/10.1096/fj.03-1100fje
Parekkadan B, Milwid JM (2010) Mesenchymal stem cells as therapeutics. Annu Rev Biomed Eng 12:87–117. https://doi.org/10.1146/annurev-bioeng-070909-105309
Horwitz EM et al (2002) Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Proc Natl Acad Sci USA 99:8932–8937. https://doi.org/10.1073/pnas.132252399
Kean TJ, Lin P, Caplan AI, Dennis JE (2013) MSCs: delivery routes and engraftment, cell-targeting strategies, and immune modulation. Stem Cells Int 2013:732742. https://doi.org/10.1155/2013/732742
Tomita M et al (2002) Bone marrow-derived stem cells can differentiate into retinal cells in injured rat retina. Stem Cells 20:279–283. https://doi.org/10.1634/stemcells.20-4-279
Inoue Y et al (2007) Subretinal transplantation of bone marrow mesenchymal stem cells delays retinal degeneration in the RCS rat model of retinal degeneration. Exp Eye Res 85:234–241. https://doi.org/10.1016/j.exer.2007.04.007
Oner A, Gonen ZB, Sinim N, Cetin M, Ozkul Y (2016) Subretinal adipose tissue-derived mesenchymal stem cell implantation in advanced stage retinitis pigmentosa: a phase I clinical safety study. Stem Cell Res Ther 7:178. https://doi.org/10.1186/s13287-016-0432-y
Satarian L et al (2017) Intravitreal injection of bone marrow mesenchymal stem cells in patients with advanced retinitis pigmentosa; a safety study. J Ophthalmic Vis Res 12:58–64. https://doi.org/10.4103/2008-322X.200164
Limoli PG, Limoli C, Vingolo EM, Scalinci SZ, Nebbioso M (2016) Cell surgery and growth factors in dry age-related macular degeneration: visual prognosis and morphological study. Oncotarget 7:46913–46923. https://doi.org/10.18632/oncotarget.10442
Uccelli A, Laroni A, Freedman MS (2011) Mesenchymal stem cells for the treatment of multiple sclerosis and other neurological diseases. Lancet Neurol 10:649–656. https://doi.org/10.1016/S1474-4422(11)70121-1
Connick P et al (2012) Autologous mesenchymal stem cells for the treatment of secondary progressive multiple sclerosis: an open-label phase 2a proof-of-concept study. Lancet Neurol 11:150–156. https://doi.org/10.1016/S1474-4422(11)70305-2
Humphreys BD, Bonventre JV (2008) Mesenchymal stem cells in acute kidney injury. Annu Rev Med 59:311–325. https://doi.org/10.1146/annurev.med.59.061506.154239
Karantalis V, Hare JM (2015) Use of mesenchymal stem cells for therapy of cardiac disease. Circ Res 116:1413–1430. https://doi.org/10.1161/CIRCRESAHA.116.303614
Volarevic V, Arsenijevic N, Lukic ML, Stojkovic M (2011) Concise review: mesenchymal stem cell treatment of the complications of diabetes mellitus. Stem Cells 29:5–10. https://doi.org/10.1002/stem.556
Kuo TK et al (2008) Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology 134:2111–2121. https://doi.org/10.1053/j.gastro.2008.03.015 (2121 e2111–2113)
Muller I, Lymperi S, Dazzi F (2008) Mesenchymal stem cell therapy for degenerative inflammatory disorders. Curr Opin Organ Transplant 13:639–644. https://doi.org/10.1097/MOT.0b013e328317a462
von Bahr L et al (2012) Analysis of tissues following mesenchymal stromal cell therapy in humans indicates limited long-term engraftment and no ectopic tissue formation. Stem Cells 30:1575–1578. https://doi.org/10.1002/stem.1118
Kurtz A (2008) Mesenchymal stem cell delivery routes and fate. Int J Stem Cells 1:1–7
Caplan AI (2007) Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J Cell Physiol 213:341–347. https://doi.org/10.1002/jcp.21200
Tuan RS, Boland G, Tuli R (2003) Adult mesenchymal stem cells and cell-based tissue engineering. Arthritis Res Ther 5:32–45
Leach JK, Whitehead J (2018) Materials-directed differentiation of mesenchymal stem cells for tissue engineering and regeneration. ACS Biomater Sci Eng 4:1115–1127. https://doi.org/10.1021/acsbiomaterials.6b00741
Loh QL, Choong C (2013) Three-dimensional scaffolds for tissue engineering applications: role of porosity and pore size. Tissue Eng Part B Rev 19:485–502. https://doi.org/10.1089/ten.TEB.2012.0437
Sheikh Z et al (2015) Biodegradable materials for bone repair and tissue engineering applications. Materials (Basel) 8:5744–5794. https://doi.org/10.3390/ma8095273
Costantini M et al (2016) 3D bioprinting of BM-MSCs-loaded ECM biomimetic hydrogels for in vitro neocartilage formation. Biofabrication 8:035002. https://doi.org/10.1088/1758-5090/8/3/035002
Aoyama T et al (2014) An exploratory clinical trial for idiopathic osteonecrosis of femoral head by cultured autologous multipotent mesenchymal stromal cells augmented with vascularized bone grafts. Tissue Eng Part B Rev 20:233–242. https://doi.org/10.1089/ten.TEB.2014.0090
Gjerde C et al (2018) Cell therapy induced regeneration of severely atrophied mandibular bone in a clinical trial. Stem Cell Res Ther 9:213. https://doi.org/10.1186/s13287-018-0951-9
Benvenuto F et al (2007) Human mesenchymal stem cells promote survival of T cells in a quiescent state. Stem Cells 25:1753–1760. https://doi.org/10.1634/stemcells.2007-0068
Morrison SJ, Scadden DT (2014) The bone marrow niche for haematopoietic stem cells. Nature 505:327–334. https://doi.org/10.1038/nature12984
Majumdar MK, Thiede MA, Haynesworth SE, Bruder SP, Gerson SL (2000) Human marrow-derived mesenchymal stem cells (MSCs) express hematopoietic cytokines and support long-term hematopoiesis when differentiated toward stromal and osteogenic lineages. J Hematother Stem Cell Res 9:841–848. https://doi.org/10.1089/152581600750062264
Hofer HR, Tuan RS (2016) Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies. Stem Cell Res Ther 7:131. https://doi.org/10.1186/s13287-016-0394-0
Greenbaum A et al (2013) CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495:227–230. https://doi.org/10.1038/nature11926
Koc ON et al (2000) Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol 18:307–316. https://doi.org/10.1200/JCO.2000.18.2.307
Watt SM et al (2013) The angiogenic properties of mesenchymal stem/stromal cells and their therapeutic potential. Br Med Bull 108:25–53. https://doi.org/10.1093/bmb/ldt031
Sacchetti B et al (2007) Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131:324–336. https://doi.org/10.1016/j.cell.2007.08.025
Pollock K et al (2016) Human mesenchymal stem cells genetically engineered to overexpress brain-derived neurotrophic factor improve outcomes in huntington’s disease mouse models. Mol Ther 24:965–977. https://doi.org/10.1038/mt.2016.12
Munoz JR, Stoutenger BR, Robinson AP, Spees JL, Prockop DJ (2005) Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice. Proc Natl Acad Sci USA 102:18171–18176. https://doi.org/10.1073/pnas.0508945102
Joyce N et al (2010) Mesenchymal stem cells for the treatment of neurodegenerative disease. Regen Med 5:933–946. https://doi.org/10.2217/rme.10.72
Crigler L, Robey RC, Asawachaicharn A, Gaupp D, Phinney DG (2006) Human mesenchymal stem cell subpopulations express a variety of neuro-regulatory molecules and promote neuronal cell survival and neuritogenesis. Exp Neurol 198:54–64. https://doi.org/10.1016/j.expneurol.2005.10.029
McCoy MK et al (2008) Autologous transplants of Adipose-Derived Adult Stromal (ADAS) cells afford dopaminergic neuroprotection in a model of Parkinson’s disease. Exp Neurol 210:14–29. https://doi.org/10.1016/j.expneurol.2007.10.011
Lin YT et al (2011) Human mesenchymal stem cells prolong survival and ameliorate motor deficit through trophic support in Huntington’s disease mouse models. PLoS One 6:e22924. https://doi.org/10.1371/journal.pone.0022924
Wakabayashi K et al (2010) Transplantation of human mesenchymal stem cells promotes functional improvement and increased expression of neurotrophic factors in a rat focal cerebral ischemia model. J Neurosci Res 88:1017–1025. https://doi.org/10.1002/jnr.22279
Wilkins A et al (2009) Human bone marrow-derived mesenchymal stem cells secrete brain-derived neurotrophic factor which promotes neuronal survival in vitro. Stem Cell Res 3:63–70. https://doi.org/10.1016/j.scr.2009.02.006
Kim KS et al (2014) Transplantation of human adipose tissue-derived stem cells delays clinical onset and prolongs life span in ALS mouse model. Cell Transplant 23:1585–1597. https://doi.org/10.3727/096368913X673450
Kim HY et al (2014) Biological markers of mesenchymal stromal cells as predictors of response to autologous stem cell transplantation in patients with amyotrophic lateral sclerosis: an investigator-initiated trial and in vivo study. Stem Cells 32:2724–2731. https://doi.org/10.1002/stem.1770
Petrou P et al (2016) Safety and clinical effects of mesenchymal stem cells secreting neurotrophic factor transplantation in patients with amyotrophic lateral sclerosis: results of phase 1/2 and 2a clinical trials. JAMA Neurol 73:337–344. https://doi.org/10.1001/jamaneurol.2015.4321
Volarevic V, Nurkovic J, Arsenijevic N, Stojkovic M (2014) Concise review: therapeutic potential of mesenchymal stem cells for the treatment of acute liver failure and cirrhosis. Stem Cells 32:2818–2823. https://doi.org/10.1002/stem.1818
Lee RH et al (2006) Multipotent stromal cells from human marrow home to and promote repair of pancreatic islets and renal glomeruli in diabetic NOD/scid mice. Proc Natl Acad Sci USA 103:17438–17443. https://doi.org/10.1073/pnas.0608249103
Morigi M, Benigni A (2013) Mesenchymal stem cells and kidney repair. Nephrol Dial Transplant 28:788–793. https://doi.org/10.1093/ndt/gfs556
Morigi M, Rota C, Remuzzi G (2016) Mesenchymal stem cells in kidney repair. Methods Mol Biol 1416:89–107. https://doi.org/10.1007/978-1-4939-3584-0_5
Zhang Y, Li Y, Zhang L, Li J, Zhu C (2018) Mesenchymal stem cells: potential application for the treatment of hepatic cirrhosis. Stem Cell Res Ther 9:59. https://doi.org/10.1186/s13287-018-0814-4
Yeung TY et al (2012) Human mesenchymal stem cells protect human islets from pro-inflammatory cytokines. PLoS One 7:e38189. https://doi.org/10.1371/journal.pone.0038189
Park KS et al (2010) Trophic molecules derived from human mesenchymal stem cells enhance survival, function, and angiogenesis of isolated islets after transplantation. Transplantation 89:509–517. https://doi.org/10.1097/TP.0b013e3181c7dc99
Chen L, Tredget EE, Wu PY, Wu Y (2008) Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One 3:e1886. https://doi.org/10.1371/journal.pone.0001886
Chen SL et al (2004) Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 94:92–95. https://doi.org/10.1016/j.amjcard.2004.03.034
Amado LC et al (2005) Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci USA 102:11474–11479. https://doi.org/10.1073/pnas.0504388102
Kinnaird T et al (2004) Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res 94:678–685. https://doi.org/10.1161/01.RES.0000118601.37875.AC
Kinnaird T et al (2004) Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 109:1543–1549. https://doi.org/10.1161/01.CIR.0000124062.31102.57
Ranganath SH, Levy O, Inamdar MS, Karp JM (2012) Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell 10:244–258. https://doi.org/10.1016/j.stem.2012.02.005
Guan XJ et al (2013) Mesenchymal stem cells protect cigarette smoke-damaged lung and pulmonary function partly via VEGF-VEGF receptors. J Cell Biochem 114:323–335. https://doi.org/10.1002/jcb.24377
Kennelly H, Mahon BP, English K (2016) Human mesenchymal stromal cells exert HGF dependent cytoprotective effects in a human relevant pre-clinical model of COPD. Sci Rep 6:38207. https://doi.org/10.1038/srep38207
Stessuk T et al (2013) Phase I clinical trial of cell therapy in patients with advanced chronic obstructive pulmonary disease: follow-up of up to 3 years. Rev Bras Hematol Hemoter 35:352–357. https://doi.org/10.5581/1516-8484.20130113
de Oliveira HG et al (2017) Combined bone marrow-derived mesenchymal stromal cell therapy and one-way endobronchial valve placement in patients with pulmonary emphysema: a phase I clinical trial. Stem Cells Transl Med 6:962–969. https://doi.org/10.1002/sctm.16-0315
Simonson OE et al (2016) In vivo effects of mesenchymal stromal cells in two patients with severe acute respiratory distress syndrome. Stem Cells Transl Med 5:845. https://doi.org/10.5966/sctm.2015-0021erratum
Karp JM, Leng Teo GS (2009) Mesenchymal stem cell homing: the devil is in the details. Cell Stem Cell 4:206–216. https://doi.org/10.1016/j.stem.2009.02.001
Eggenhofer E, Luk F, Dahlke MH, Hoogduijn MJ (2014) The life and fate of mesenchymal stem cells. Front Immunol 5:148. https://doi.org/10.3389/fimmu.2014.00148
Li M et al (2016) In vivo human adipose-derived mesenchymal stem cell tracking after intra-articular delivery in a rat osteoarthritis model. Stem Cell Res Ther 7:160. https://doi.org/10.1186/s13287-016-0420-2
Brooks A et al (2018) Concise review: quantitative detection and modeling the in vivo kinetics of therapeutic mesenchymal stem/stromal cells. Stem Cells Transl Med 7:78–86. https://doi.org/10.1002/sctm.17-0209
Sohni A, Verfaillie CM (2013) Mesenchymal stem cells migration homing and tracking. Stem Cells Int 2013:130763. https://doi.org/10.1155/2013/130763
Ruster B et al (2006) Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells. Blood 108:3938–3944. https://doi.org/10.1182/blood-2006-05-025098
Thankamony SP, Sackstein R (2011) Enforced hematopoietic cell E- and L-selectin ligand (HCELL) expression primes transendothelial migration of human mesenchymal stem cells. Proc Natl Acad Sci USA 108:2258–2263. https://doi.org/10.1073/pnas.1018064108
Nitzsche F et al (2017) Concise review: MSC adhesion cascade-insights into homing and transendothelial migration. Stem Cells 35:1446–1460. https://doi.org/10.1002/stem.2614
Fox JM, Chamberlain G, Ashton BA, Middleton J (2007) Recent advances into the understanding of mesenchymal stem cell trafficking. Br J Haematol 137:491–502. https://doi.org/10.1111/j.1365-2141.2007.06610.x
Laird DJ, von Andrian UH, Wagers AJ (2008) Stem cell trafficking in tissue development, growth, and disease. Cell 132:612–630. https://doi.org/10.1016/j.cell.2008.01.041
Leibacher J, Henschler R (2016) Biodistribution, migration and homing of systemically applied mesenchymal stem/stromal cells. Stem Cell Res Ther 7:7. https://doi.org/10.1186/s13287-015-0271-2
Aldridge V et al (2012) Human mesenchymal stem cells are recruited to injured liver in a beta1-integrin and CD44 dependent manner. Hepatology 56:1063–1073. https://doi.org/10.1002/hep.25716
Kumar S, Ponnazhagan S (2007) Bone homing of mesenchymal stem cells by ectopic alpha 4 integrin expression. FASEB J 21:3917–3927. https://doi.org/10.1096/fj.07-8275com
Semon JA et al (2010) Integrin expression and integrin-mediated adhesion in vitro of human multipotent stromal cells (MSCs) to endothelial cells from various blood vessels. Cell Tissue Res 341:147–158. https://doi.org/10.1007/s00441-010-0994-4
Ringe J et al (2007) Towards in situ tissue repair: human mesenchymal stem cells express chemokine receptors CXCR238, CXCR238 and CCR238, and migrate upon stimulation with CXCL8 but not CCL2. J Cell Biochem 101:135–146. https://doi.org/10.1002/jcb.21172
Ponte AL et al (2007) The in vitro migration capacity of human bone marrow mesenchymal stem cells: comparison of chemokine and growth factor chemotactic activities. Stem Cells 25:1737–1745. https://doi.org/10.1634/stemcells.2007-0054
Wynn RF et al (2004) A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR240 receptor capable of promoting migration to bone marrow. Blood 104:2643–2645. https://doi.org/10.1182/blood-2004-02-0526
Ziaei R, Ayatollahi M, Yaghobi R, Sahraeian Z, Zarghami N (2014) Involvement of TNF-alpha in differential gene expression pattern of CXCR241 on human marrow-derived mesenchymal stem cells. Mol Biol Rep 41:1059–1066. https://doi.org/10.1007/s11033-013-2951-2
Fan H et al (2012) Pre-treatment with IL-1beta enhances the efficacy of MSC transplantation in DSS-induced colitis. Cell Mol Immunol 9:473–481. https://doi.org/10.1038/cmi.2012.40
Park SA et al (2011) CXCR243-transfected human umbilical cord blood-derived mesenchymal stem cells exhibit enhanced migratory capacity toward gliomas. Int J Oncol 38:97–103
Ries C et al (2007) MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines. Blood 109:4055–4063. https://doi.org/10.1182/blood-2006-10-051060
Ho IA et al (2009) Matrix metalloproteinase 1 is necessary for the migration of human bone marrow-derived mesenchymal stem cells toward human glioma. Stem Cells 27:1366–1375. https://doi.org/10.1002/stem.50
Kim Y et al (2007) Direct comparison of human mesenchymal stem cells derived from adipose tissues and bone marrow in mediating neovascularization in response to vascular ischemia. Cell Physiol Biochem 20:867–876. https://doi.org/10.1159/000110447
Gholamrezanezhad A et al (2011) In vivo tracking of 111In-oxine labeled mesenchymal stem cells following infusion in patients with advanced cirrhosis. Nucl Med Biol 38:961–967. https://doi.org/10.1016/j.nucmedbio.2011.03.008
Fischer UM et al (2009) Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev 18:683–692. https://doi.org/10.1089/scd.2008.0253
Argibay B et al (2017) Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia. Sci Rep 7:40758. https://doi.org/10.1038/srep40758
Di Nicola M et al (2002) Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99:3838–3843
Chinnadurai R, Copland IB, Patel SR, Galipeau J (2014) IDO-independent suppression of T cell effector function by IFN-gamma-licensed human mesenchymal stromal cells. J Immunol 192:1491–1501. https://doi.org/10.4049/jimmunol.1301828
Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F (2005) Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105:2821–2827. https://doi.org/10.1182/blood-2004-09-3696
Ryan JM, Barry F, Murphy JM, Mahon BP (2007) Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol 149:353–363. https://doi.org/10.1111/j.1365-2249.2007.03422.x
Boland L et al (2018) IFN-gamma and TNF-alpha pre-licensing protects mesenchymal stromal cells from the pro-inflammatory effects of palmitate. Mol Ther 26:860–873. https://doi.org/10.1016/j.ymthe.2017.12.013
Krampera M (2011) Mesenchymal stromal cell ‘licensing’: a multistep process. Leukemia 25:1408–1414. https://doi.org/10.1038/leu.2011.108
Gao F et al (2016) Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis 7:e2062. https://doi.org/10.1038/cddis.2015.327
Corcione A et al (2006) Human mesenchymal stem cells modulate B-cell functions. Blood 107:367–372. https://doi.org/10.1182/blood-2005-07-2657
Selmani Z et al (2008) Human leukocyte antigen-G5 secretion by human mesenchymal stem cells is required to suppress T lymphocyte and natural killer function and to induce CD4+ CD25highFOXP3+ regulatory T cells. Stem Cells 26:212–222. https://doi.org/10.1634/stemcells.2007-0554
Spaggiari GM et al (2008) Mesenchymal stem cells inhibit natural killer-cell proliferation, cytotoxicity, and cytokine production: role of indoleamine 2,3-dioxygenase and prostaglandin E2. Blood 111:1327–1333. https://doi.org/10.1182/blood-2007-02-074997
Jiang XX et al (2005) Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105:4120–4126. https://doi.org/10.1182/blood-2004-02-0586
Ramasamy R et al (2007) Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. Transplantation 83:71–76. https://doi.org/10.1097/01.tp.0000244572.24780.54
Ylostalo JH, Bartosh TJ, Coble K, Prockop DJ (2012) Human mesenchymal stem/stromal cells cultured as spheroids are self-activated to produce prostaglandin E2 that directs stimulated macrophages into an anti-inflammatory phenotype. Stem Cells 30:2283–2296. https://doi.org/10.1002/stem.1191
Ghannam S, Pene J, Moquet-Torcy G, Jorgensen C, Yssel H (2010) Mesenchymal stem cells inhibit human Th17 cell differentiation and function and induce a T regulatory cell phenotype. J Immunol 185:302–312. https://doi.org/10.4049/jimmunol.0902007
Rozenberg A et al (2016) Human mesenchymal stem cells impact Th17 and Th1 responses through a prostaglandin E2 and myeloid-dependent mechanism. Stem Cells Transl Med 5:1506–1514. https://doi.org/10.5966/sctm.2015-0243
Bai L et al (2009) Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 57:1192–1203. https://doi.org/10.1002/glia.20841
Nauta AJ, Kruisselbrink AB, Lurvink E, Willemze R, Fibbe WE (2006) Mesenchymal stem cells inhibit generation and function of both CD34+-derived and monocyte-derived dendritic cells. J Immunol 177:2080–2087
Luz-Crawford P et al (2013) Mesenchymal stem cells generate a CD4+ CD25+ Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res Ther 4:65. https://doi.org/10.1186/scrt216
Liu Q et al (2015) Human mesenchymal stromal cells enhance the immunomodulatory function of CD8(+)CD28(−) regulatory T cells. Cell Mol Immunol 12:708–718. https://doi.org/10.1038/cmi.2014.118
Cho KA et al (2017) Mesenchymal stem cells ameliorate B-cell-mediated immune responses and increase IL-10-expressing regulatory B cells in an EBI3-dependent manner. Cell Mol Immunol 14:895. https://doi.org/10.1038/cmi.2016.59
Liu X et al (2012) Mesenchymal stem/stromal cells induce the generation of novel IL-10-dependent regulatory dendritic cells by SOCS3 activation. J Immunol 189:1182–1192. https://doi.org/10.4049/jimmunol.1102996
Kim J, Hematti P (2009) Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. Exp Hematol 37:1445–1453. https://doi.org/10.1016/j.exphem.2009.09.004
Uccelli A, Moretta L, Pistoia V (2008) Mesenchymal stem cells in health and disease. Nat Rev Immunol 8:726–736. https://doi.org/10.1038/nri2395
Le Blanc K, Ringden O (2005) Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 11:321–334. https://doi.org/10.1016/j.bbmt.2005.01.005
Nauta AJ, Fibbe WE (2007) Immunomodulatory properties of mesenchymal stromal cells. Blood 110:3499–3506. https://doi.org/10.1182/blood-2007-02-069716
Le Blanc K et al (2008) Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371:1579–1586. https://doi.org/10.1016/S0140-6736(08)60690-X
Le Blanc K et al (2004) Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 363:1439–1441. https://doi.org/10.1016/S0140-6736(04)16104-7
Tan J et al (2012) Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA 307:1169–1177. https://doi.org/10.1001/jama.2012.316
Peng Y et al (2013) Donor-derived mesenchymal stem cells combined with low-dose tacrolimus prevent acute rejection after renal transplantation: a clinical pilot study. Transplantation 95:161–168. https://doi.org/10.1097/TP.0b013e3182754c53
Hartleif S et al (2017) Safety and tolerance of donor-derived mesenchymal stem cells in pediatric living-donor liver transplantation: the MYSTEP1 study. Stem Cells Int 2017:2352954. https://doi.org/10.1155/2017/2352954
Perico N et al (2011) Autologous mesenchymal stromal cells and kidney transplantation: a pilot study of safety and clinical feasibility. Clin J Am Soc Nephrol 6:412–422. https://doi.org/10.2215/CJN.04950610
Reinders ME et al (2013) Autologous bone marrow-derived mesenchymal stromal cells for the treatment of allograft rejection after renal transplantation: results of a phase I study. Stem Cells Transl Med 2:107–111. https://doi.org/10.5966/sctm.2012-0114
Pan GH et al (2016) Low-dose tacrolimus combined with donor-derived mesenchymal stem cells after renal transplantation: a prospective, non-randomized study. Oncotarget 7:12089–12101. https://doi.org/10.18632/oncotarget.7725
Detry O et al (2017) Infusion of mesenchymal stromal cells after deceased liver transplantation: a phase I–II, open-label, clinical study. J Hepatol 67:47–55. https://doi.org/10.1016/j.jhep.2017.03.001
Soeder Y et al (2015) First-in-human case study: multipotent adult progenitor cells for immunomodulation after liver transplantation. Stem Cells Transl Med 4:899–904. https://doi.org/10.5966/sctm.2015-0002
Mao F et al (2017) Mesenchymal stem cells and their therapeutic applications in inflammatory bowel disease. Oncotarget 8:38008–38021. https://doi.org/10.18632/oncotarget.16682
Duijvestein M et al (2010) Autologous bone marrow-derived mesenchymal stromal cell treatment for refractory luminal Crohn’s disease: results of a phase I study. Gut 59:1662–1669. https://doi.org/10.1136/gut.2010.215152
Ciccocioppo R et al (2011) Autologous bone marrow-derived mesenchymal stromal cells in the treatment of fistulising Crohn’s disease. Gut 60:788–798. https://doi.org/10.1136/gut.2010.214841
Forbes GM et al (2014) A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn’s disease refractory to biologic therapy. Clin Gastroenterol Hepatol 12:64–71. https://doi.org/10.1016/j.cgh.2013.06.021
Alvaro-Gracia JM et al (2017) Intravenous administration of expanded allogeneic adipose-derived mesenchymal stem cells in refractory rheumatoid arthritis (Cx611): results of a multicentre, dose escalation, randomised, single-blind, placebo-controlled phase Ib/IIa clinical trial. Ann Rheum Dis 76:196–202. https://doi.org/10.1136/annrheumdis-2015-208918
Djouad F, Bouffi C, Ghannam S, Noel D, Jorgensen C (2009) Mesenchymal stem cells: innovative therapeutic tools for rheumatic diseases. Nat Rev Rheumatol 5:392–399. https://doi.org/10.1038/nrrheum.2009.104
Gonzalez-Rey E et al (2010) Human adipose-derived mesenchymal stem cells reduce inflammatory and T cell responses and induce regulatory T cells in vitro in rheumatoid arthritis. Ann Rheum Dis 69:241–248. https://doi.org/10.1136/ard.2008.101881
Panes J et al (2018) Long-term efficacy and safety of stem cell therapy (Cx601) for complex perianal fistulas in patients with Crohn’s disease. Gastroenterology 154:1334–1342 e1334. https://doi.org/10.1053/j.gastro.2017.12.020
Wang D et al (2018) A long-term follow-up study of allogeneic mesenchymal stem/stromal cell transplantation in patients with drug-resistant systemic lupus erythematosus. Stem Cell Rep 10:933–941. https://doi.org/10.1016/j.stemcr.2018.01.029
Roddy GW et al (2011) Action at a distance: systemically administered adult stem/progenitor cells (MSCs) reduce inflammatory damage to the cornea without engraftment and primarily by secretion of TNF-alpha stimulated gene/protein 6. Stem Cells 29:1572–1579. https://doi.org/10.1002/stem.708
De Becker A, Riet IV (2016) Homing and migration of mesenchymal stromal cells: how to improve the efficacy of cell therapy? World J Stem Cells 8:73–87. https://doi.org/10.4252/wjsc.v8.i3.73
Cselenyak A, Pankotai E, Horvath EM, Kiss L, Lacza Z (2010) Mesenchymal stem cells rescue cardiomyoblasts from cell death in an in vitro ischemia model via direct cell-to-cell connections. BMC Cell Biol 11:29. https://doi.org/10.1186/1471-2121-11-29
Kong D et al (2017) Mesenchymal stem cells protect neurons against hypoxic-ischemic injury via inhibiting parthanatos, necroptosis, and apoptosis, but not autophagy. Cell Mol Neurobiol 37:303–313. https://doi.org/10.1007/s10571-016-0370-3
Mahrouf-Yorgov M et al (2017) Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties. Cell Death Differ 24:1224–1238. https://doi.org/10.1038/cdd.2017.51
Naji A et al (2016) Endocytosis of indium-tin-oxide nanoparticles by macrophages provokes pyroptosis requiring NLRP3-ASC-Caspase1 axis that can be prevented by mesenchymal stem cells. Sci Rep 6:26162. https://doi.org/10.1038/srep26162
Scheibe F, Klein O, Klose J, Priller J (2012) Mesenchymal stromal cells rescue cortical neurons from apoptotic cell death in an in vitro model of cerebral ischemia. Cell Mol Neurobiol 32:567–576. https://doi.org/10.1007/s10571-012-9798-2
Zhao K et al (2015) Bone marrow-derived mesenchymal stem cells ameliorate chronic high glucose-induced beta-cell injury through modulation of autophagy. Cell Death Dis 6:e1885. https://doi.org/10.1038/cddis.2015.230
Zilka N et al (2011) Mesenchymal stem cells rescue the Alzheimer’s disease cell model from cell death induced by misfolded truncated tau. Neuroscience 193:330–337. https://doi.org/10.1016/j.neuroscience.2011.06.088
Kratchmarova I, Blagoev B, Haack-Sorensen M, Kassem M, Mann M (2005) Mechanism of divergent growth factor effects in mesenchymal stem cell differentiation. Science 308:1472–1477. https://doi.org/10.1126/science.1107627
Platt MO, Roman AJ, Wells A, Lauffenburger DA, Griffith LG (2009) Sustained epidermal growth factor receptor levels and activation by tethered ligand binding enhances osteogenic differentiation of multi-potent marrow stromal cells. J Cell Physiol 221:306–317. https://doi.org/10.1002/jcp.21854
Miraoui H et al (2009) Fibroblast growth factor receptor 2 promotes osteogenic differentiation in mesenchymal cells via ERK1/2 and protein kinase C signaling. J Biol Chem 284:4897–4904. https://doi.org/10.1074/jbc.M805432200
Scavo LM, Karas M, Murray M, Leroith D (2004) Insulin-like growth factor-I stimulates both cell growth and lipogenesis during differentiation of human mesenchymal stem cells into adipocytes. J Clin Endocrinol Metab 89:3543–3553. https://doi.org/10.1210/jc.2003-031682
Roelen BA, Dijke P (2003) Controlling mesenchymal stem cell differentiation by TGFBeta family members. J Orthop Sci 8:740–748. https://doi.org/10.1007/s00776-003-0702-2
Maeda S, Hayashi M, Komiya S, Imamura T, Miyazono K (2004) Endogenous TGF-beta signaling suppresses maturation of osteoblastic mesenchymal cells. EMBO J 23:552–563. https://doi.org/10.1038/sj.emboj.7600067
Oliveira FS et al (2012) Hedgehog signaling and osteoblast gene expression are regulated by purmorphamine in human mesenchymal stem cells. J Cell Biochem 113:204–208. https://doi.org/10.1002/jcb.23345
Chang J et al (2007) Noncanonical Wnt-4 signaling enhances bone regeneration of mesenchymal stem cells in craniofacial defects through activation of p38 MAPK. J Biol Chem 282:30938–30948. https://doi.org/10.1074/jbc.M702391200
Ugarte F et al (2009) Notch signaling enhances osteogenic differentiation while inhibiting adipogenesis in primary human bone marrow stromal cells. Exp Hematol 37:867–875 e861. https://doi.org/10.1016/j.exphem.2009.03.007
Zhou S (2011) TGF-beta regulates beta-catenin signaling and osteoblast differentiation in human mesenchymal stem cells. J Cell Biochem 112:1651–1660. https://doi.org/10.1002/jcb.23079
Qian SW et al (2010) Characterization of adipocyte differentiation from human mesenchymal stem cells in bone marrow. BMC Dev Biol 10:47. https://doi.org/10.1186/1471-213X-10-47
Thiagarajan L, Abu-Awwad HAM, Dixon JE (2017) Osteogenic programming of human mesenchymal stem cells with highly efficient intracellular delivery of RUNX2. Stem Cells Transl Med 6:2146–2159. https://doi.org/10.1002/sctm.17-0137
Xu J, Li Z, Hou Y, Fang W (2015) Potential mechanisms underlying the Runx2 induced osteogenesis of bone marrow mesenchymal stem cells. Am J Transl Res 7:2527–2535
Yu WH et al (2012) PPARgamma suppression inhibits adipogenesis but does not promote osteogenesis of human mesenchymal stem cells. Int J Biochem Cell Biol 44:377–384. https://doi.org/10.1016/j.biocel.2011.11.013
Zhu F, Friedman MS, Luo W, Woolf P, Hankenson KD (2012) The transcription factor osterix (SP7) regulates BMP6-induced human osteoblast differentiation. J Cell Physiol 227:2677–2685. https://doi.org/10.1002/jcp.23010
Pedersen TO et al (2014) Mesenchymal stem cells induce endothelial cell quiescence and promote capillary formation. Stem Cell Res Ther 5:23. https://doi.org/10.1186/scrt412
Kingham PJ, Kolar MK, Novikova LN, Novikov LN, Wiberg M (2014) Stimulating the neurotrophic and angiogenic properties of human adipose-derived stem cells enhances nerve repair. Stem Cells Dev 23:741–754. https://doi.org/10.1089/scd.2013.0396
Li D et al (2013) Mesenchymal stem cells protect podocytes from apoptosis induced by high glucose via secretion of epithelial growth factor. Stem Cell Res Ther 4:103. https://doi.org/10.1186/scrt314
Ding C et al (2018) Human amniotic mesenchymal stem cells improve ovarian function in natural aging through secreting hepatocyte growth factor and epidermal growth factor. Stem Cell Res Ther 9:55. https://doi.org/10.1186/s13287-018-0781-9
Zwezdaryk KJ et al (2007) Erythropoietin, a hypoxia-regulated factor, elicits a pro-angiogenic program in human mesenchymal stem cells. Exp Hematol 35:640–652
Hu X et al (2008) Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. J Thorac Cardiovasc Surg 135:799–808
Wu L, Leijten J, van Blitterswijk CA, Karperien M (2013) Fibroblast growth factor-1 is a mesenchymal stromal cell-secreted factor stimulating proliferation of osteoarthritic chondrocytes in co-culture. Stem Cells Dev 22:2356–2367. https://doi.org/10.1089/scd.2013.0118
Zhang Z, Wang Y, Li M, Li J, Wu J (2014) Fibroblast growth factor 18 increases the trophic effects of bone marrow mesenchymal stem cells on chondrocytes isolated from late stage osteoarthritic patients. Stem Cells Int 2014:125643. https://doi.org/10.1155/2014/125683
Horita Y et al (2006) Intravenous administration of glial cell line-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in the adult rat. J Neurosci Res 84:1495–1504
Ding D-C et al (2007) Enhancement of neuroplasticity through upregulation of β1-integrin in human umbilical cord-derived stromal cell implanted stroke model. Neurobiol Dis 27:339–353
Jeong CH et al (2014) Mesenchymal stem cells expressing brain-derived neurotrophic factor enhance endogenous neurogenesis in an ischemic stroke model. Biomed Res Int 2014:129145. https://doi.org/10.1155/2014/129145
Neuss S, Becher E, Woltje M, Tietze L, Jahnen-Dechent W (2004) Functional expression of HGF and HGF receptor/c-met in adult human mesenchymal stem cells suggests a role in cell mobilization, tissue repair, and wound healing. Stem Cells 22:405–414. https://doi.org/10.1634/stemcells.22-3-405
Zhang J et al (2004) Expression of insulin-like growth factor 1 and receptor in ischemic rats treated with human marrow stromal cells. Brain Res 1030:19–27
Tfilin M et al (2010) Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior. Mol Psychiatry 15:1164–1175. https://doi.org/10.1038/mp.2009.110
Casey ML, MacDonald PC (1997) Keratinocyte growth factor expression in the mesenchymal cells of human amnion. J Clin Endocrinol Metab 82:3319–3323. https://doi.org/10.1210/jcem.82.10.4294
Zhu YG et al (2014) Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem cells 32:116–125
Ding W et al (2010) Platelet-derived growth factor (PDGF)–PDGF receptor interaction activates bone marrow–derived mesenchymal stromal cells derived from chronic lymphocytic leukemia: implications for an angiogenic switch. Blood 116:2984–2993
Osborne A, Sanderson J, Martin KR (2018) Neuroprotective effects of human mesenchymal stem cells and platelet-derived growth factor on human retinal ganglion cells. Stem Cells 36:65–78
Mishra PJ et al (2008) Carcinoma-associated fibroblast–like differentiation of human mesenchymal stem cells. Can Res 68:4331–4339
Mayer H et al (2005) Vascular endothelial growth factor (VEGF-A) expression in human mesenchymal stem cells: autocrine and paracrine role on osteoblastic and endothelial differentiation. J Cell Biochem 95:827–839. https://doi.org/10.1002/jcb.20462
Beckermann BM et al (2008) VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma. Br J Cancer 99:622–631. https://doi.org/10.1038/sj.bjc.6604508
Herrera MB et al (2007) Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury. Kidney Int 72:430–441. https://doi.org/10.1038/sj.ki.5002334
Popov C et al (2011) Integrins alpha2beta1 and alpha11beta1 regulate the survival of mesenchymal stem cells on collagen I. Cell Death Dis 2:e186. https://doi.org/10.1038/cddis.2011.71
Frith JE, Mills RJ, Hudson JE, Cooper-White JJ (2012) Tailored integrin–extracellular matrix interactions to direct human mesenchymal stem cell differentiation. Stem Cells Dev 21:2442–2456
Veevers-Lowe J, Ball SG, Shuttleworth A, Kielty CM (2011) Mesenchymal stem cell migration is regulated by fibronectin through α5β1-integrin-mediated activation of PDGFR-β and potentiation of growth factor signals. J Cell Sci 124:1288–1300
Lüttichau IV et al (2005) Human adult CD34− progenitor cells functionally express the chemokine receptors CCR344, CCR344, CCR344, CXCR344, and CCR344 but not CXCR344. Stem cells and development 14:329–336
Baek SJ, Kang SK, Ra JC (2011) In vitro migration capacity of human adipose tissue-derived mesenchymal stem cells reflects their expression of receptors for chemokines and growth factors. Exp Mol Med 43:596
Jung Y et al (2013) Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis. Nat Commun 4:1795
Lu C, Li X-Y, Hu Y, Rowe RG, Weiss SJ (2010) MT1-MMP controls human mesenchymal stem cell trafficking and differentiation. Blood 115:221–229
Egea V et al (2012) Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/β-catenin signaling. Proc Natl Acad Sci 109:E309–E316
Chelluboina B et al (2017) Mesenchymal stem cell treatment prevents post-stroke dysregulation of matrix metalloproteinases and tissue inhibitors of metalloproteinases. Cell Physiol Biochem 44:1360–1369
Najar M et al (2009) Mesenchymal stromal cells promote or suppress the proliferation of T lymphocytes from cord blood and peripheral blood: the importance of low cell ratio and role of interleukin-6. Cytotherapy 11:570–583. https://doi.org/10.1080/14653240903079377
Beyth S et al (2005) Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 105:2214–2219. https://doi.org/10.1182/blood-2004-07-2921
Rasmusson I, Ringden O, Sundberg B, Le Blanc K (2005) Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms. Exp Cell Res 305:33–41. https://doi.org/10.1016/j.yexcr.2004.12.013
Nasef A et al (2008) Leukemia inhibitory factor: role in human mesenchymal stem cells mediated immunosuppression. Cell Immunol 253:16–22. https://doi.org/10.1016/j.cellimm.2008.06.002
Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M (2006) Interactions between human mesenchymal stem cells and natural killer cells. Stem cells 24:74–85
Patel SA et al (2010) Mesenchymal stem cells protect breast cancer cells through regulatory T cells: role of mesenchymal stem cell-derived TGF-β. J Immunol 184:5885–5894
Choi H, Lee RH, Bazhanov N, Oh JY, Prockop DJ (2011) Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-kappaB signaling in resident macrophages. Blood 118:330–338. https://doi.org/10.1182/blood-2010-12-327353
Mougiakakos D et al (2011) The impact of inflammatory licensing on heme oxygenase-1-mediated induction of regulatory T cells by human mesenchymal stem cells. Blood 117:4826–4835. https://doi.org/10.1182/blood-2010-12-324038
Francois M, Romieu-Mourez R, Li M, Galipeau J (2012) Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol Ther 20:187–195. https://doi.org/10.1038/mt.2011.189
Ren G et al (2009) Species variation in the mechanisms of mesenchymal stem cell-mediated immunosuppression. Stem Cells 27:1954–1962. https://doi.org/10.1002/stem.118
Spaggiari GM, Abdelrazik H, Becchetti F, Moretta L (2009) MSCs inhibit monocyte-derived DC maturation and function by selectively interfering with the generation of immature DCs: central role of MSC-derived prostaglandin E2. Blood 113:6576–6583. https://doi.org/10.1182/blood-2009-02-203943
Gieseke F et al (2010) Human multipotent mesenchymal stromal cells use galectin-1 to inhibit immune effector cells. Blood 116:3770–3779. https://doi.org/10.1182/blood-2010-02-270777
Lepelletier Y et al (2010) Galectin-1 and semaphorin-3A are two soluble factors conferring T-cell immunosuppression to bone marrow mesenchymal stem cell. Stem Cells Dev 19:1075–1079. https://doi.org/10.1089/scd.2009.0212
Espagnolle N, Balguerie A, Arnaud E, Sensebe L, Varin A (2017) CD54-mediated interaction with pro-inflammatory macrophages increases the immunosuppressive function of human mesenchymal stromal cells. Stem Cell Reports 8:961–976. https://doi.org/10.1016/j.stemcr.2017.02.008
Yang ZX et al (2013) CD106 identifies a subpopulation of mesenchymal stem cells with unique immunomodulatory properties. PLoS One 8:e59354. https://doi.org/10.1371/journal.pone.0059354
Davies LC, Heldring N, Kadri N, Le Blanc K (2017) Mesenchymal stromal cell secretion of programmed death-1 ligands regulates T cell mediated immunosuppression. Stem Cells 35:766–776. https://doi.org/10.1002/stem.2509
Tipnis S, Viswanathan C, Majumdar AS (2010) Immunosuppressive properties of human umbilical cord-derived mesenchymal stem cells: role of B7-H1 and IDO. Immunol Cell Biol 88:795–806. https://doi.org/10.1038/icb.2010.47
Xue Q et al (2010) The negative co-signaling molecule b7-h4 is expressed by human bone marrow-derived mesenchymal stem cells and mediates its T-cell modulatory activity. Stem Cells Dev 19:27–38. https://doi.org/10.1089/scd.2009.0076
Gu YZ et al (2013) Different roles of PD-L1 and FasL in immunomodulation mediated by human placenta-derived mesenchymal stem cells. Hum Immunol 74:267–276. https://doi.org/10.1016/j.humimm.2012.12.011
Acknowledgements
Support for research was provided by Suzuken Memorial Foundation (Japan) and the Japanese Society for the Promotion of Science (JSPS), Young B KAKENHI (Grant No. 17K15729) to A.N.
Author information
Authors and Affiliations
Contributions
AN and NS contributed to establishing the concept convoyed in the manuscript. AN wrote the manuscript and designed figures and tables. ME, BF, FD, NRF and NS contributed to the writing and editing of the manuscript. All authors reviewed the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Naji, A., Eitoku, M., Favier, B. et al. Biological functions of mesenchymal stem cells and clinical implications. Cell. Mol. Life Sci. 76, 3323–3348 (2019). https://doi.org/10.1007/s00018-019-03125-1
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00018-019-03125-1