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Bone-Marrow-Derived Mesenchymal Stromal Cells: From Basic Biology to Applications in Bone Tissue Engineering and Bone Regeneration

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Cell Engineering and Regeneration

Part of the book series: Reference Series in Biomedical Engineering ((TIENRE))

Abstract

Bone marrow provides a rich source of mesenchymal stromal cells (MSCs), which have the remarkable capacity for cell and tissue regeneration. Since their initial discovery in the guinea pig almost 50 years ago, bone-marrow-derived MSCs have been extensively studied in animals and humans. Several subpopulations have been characterized with the aim to isolate, enrich, and identify the cells with stem-cell properties and immunomodulatory actions, which are important for regenerative medicine. In this chapter, we review the properties of bone-marrow-derived MSCs with a focus on the preclinical setting and discuss their applications for bone tissue engineering and bone regeneration.

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References

  • Agata H, Watanabe N, Ishii Y, Kubo N, Ohshima S, Yamazaki M, Tojo A, Kagami H (2009) Feasibility and efficacy of bone tissue engineering using human bone marrow stromal cells cultivated in serum-free conditions. Biochem Biophys Res Commun. https://doi.org/10.1016/j.bbrc.2009.03.023

  • Ancans J (2012) Cell therapy medicinal product regulatory framework in Europe and its application for MSC-based therapy development. Front Immunol 3:253

    PubMed  PubMed Central  Google Scholar 

  • Beloti MM, Sicchieri LG, De Oliveira PT, Rosa AL (2012) The influence of osteoblast differentiation stage on bone formation in autogenously implanted cell-based poly(lactide-co-glycolide) and calcium phosphate constructs. Tissue Eng Part A. https://doi.org/10.1089/ten.tea.2011.0405

  • Bernardo ME, Zaffaroni N, Novara F, Cometa AM, Avanzini MA, Moretta A, Montagna D, Maccario R, Villa R, Daidone MG, Zuffardi O, Locatelli F (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. https://doi.org/10.1158/0008-5472.CAN-06-4690

  • Bhumiratana S, Eton RE, Oungoulian SR, Wan LQ, Ateshian GA, Vunjak-Novakovic G (2014) Large, stratified, and mechanically functional human cartilage grown in vitro by mesenchymal condensation. Proc Natl Acad Sci USA 111:6940–6945. https://doi.org/10.1073/pnas.1324050111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bianchi G, Banfi A, Mastrogiacomo M, Notaro R, Luzzatto L, Cancedda R, Quarto R (2003) Ex vivo enrichment of mesenchymal cell progenitors by fibroblast growth factor 2. Exp Cell Res 287:98–105. https://doi.org/10.1016/S0014-4827(03)00138-1

    Article  CAS  PubMed  Google Scholar 

  • Boskey AL (2013) Bone composition: relationship to bone fragility and antiosteoporotic drug effects. Bonekey Rep. https://doi.org/10.1038/bonekey.2013.181

  • Bourin P, Bunnell BA, Casteilla L, Dominici M, Katz AJ, March KL, Redl H, Rubin JP, Yoshimura K, Gimble JM (2013) Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy 15:641–648. https://doi.org/10.1016/j.jcyt.2013.02.006

    Article  PubMed  PubMed Central  Google Scholar 

  • Bruder SP, Kraus KH, Goldberg VM, Kadiyala S (1998) The effect of implants loaded with autologous mesenchymal stem cells on the healing of canine segmental bone defects. J Bone Jt Surg A. https://doi.org/10.2106/00004623-199807000-00007

  • Čamernik K, Barlič A, Drobnič M, Marc J, Jeras M, Zupan J (2018) Mesenchymal stem cells in the musculoskeletal system: from animal models to human tissue regeneration? Stem Cell Rev Rep 14:346–369. https://doi.org/10.1007/s12015-018-9800-6

    Article  CAS  PubMed  Google Scholar 

  • Campbell TM, Churchman SM, Gomez A, Mcgonagle D, Conaghan PG, Ponchel F, Jones E (2016) Mesenchymal stem cell alterations in bone marrow lesions in patients with hip osteoarthritis. Arthritis Rheumatol 68:1648–1659. https://doi.org/10.1002/art.39622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caplan AI (1991) Mesenchymal stem cells. J Orthop Res 9:641–650. https://doi.org/10.1002/jor.1100090504

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  Google Scholar 

  • Caralla T, Joshi P, Fleury S, Luangphakdy V, Shinohara K, Pan H, Boehm C, Vasanji A, Hefferan TE, Walker E, Yaszemski M, Hascall V, Zborowski M, Muschler GF (2013) In vivo transplantation of autogenous marrow-derived cells following rapid intraoperative magnetic separation based on hyaluronan to augment bone regeneration. Tissue Eng Part A. https://doi.org/10.1089/ten.tea.2011.0622

  • Cattaneo P, Sun Y, Moore-morris T, Dalton ND, Rockenstein E, Masliah E, Peterson KL, Stallcup B, Chen J, Evans SM, Jolla L, Hospital E, Jolla L, Jolla L, Program CI, Burnham S, Jolla L, Jolla L (2018) Pericytes of multiple organs. Cell Stem Cell 20:345–359. https://doi.org/10.1016/j.stem.2016.12.006.Pericytes

    Article  Google Scholar 

  • Cavallo C, Cuomo C, Fantini S, Ricci F, Tazzari PL, Lucarelli E, Donati D, Facchini A, Lisignoli G, Fornasari PM, Grigolo B, Moroni L (2011) Comparison of alternative mesenchymal stem cell sources for cell banking and musculoskeletal advanced therapies. J Cell Biochem 112:1418–1430. https://doi.org/10.1002/jcb.23058

    Article  CAS  PubMed  Google Scholar 

  • Chahal J, Gómez-Aristizábal A, Shestopaloff K, Bhatt S, Chaboureau A, Fazio A, Chisholm J, Weston A, Chiovitti J, Keating A, Kapoor M, Ogilvie-Harris DJ, Syed KA, Gandhi R, Mahomed NN, Marshall KW, Sussman MS, Naraghi AM, Viswanathan S (2019) Bone marrow mesenchymal stromal cell treatment in patients with osteoarthritis results in overall improvement in pain and symptoms and reduces synovial inflammation. Stem Cells Transl Med 8:746–757. https://doi.org/10.1002/sctm.18-0183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan CKF, Seo EY, Chen JY, Lo D, McArdle A, Sinha R, Tevlin R, Seita J, Vincent-Tompkins J, Wearda T, Lu WJ, Senarath-Yapa K, Chung MT, Marecic O, Tran M, Yan KS, Upton R, Walmsley GG, Lee AS, Sahoo D, Kuo CJ, Weissman IL, Longaker MT (2015) Identification and specification of the mouse skeletal stem cell. Cell 160:285–298. https://doi.org/10.1016/j.cell.2014.12.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan CKF, Gulati GS, Sinha R, Tompkins JV, Lopez M, Carter AC, Ransom RC, Reinisch A, Wearda T, Murphy M, Brewer RE, Koepke LS, Marecic O, Manjunath A, Seo EY, Leavitt T, Lu W-J, Nguyen A, Conley SD, Salhotra A, Ambrosi TH, Borrelli MR, Siebel T, Chan K, Schallmoser K, Seita J, Sahoo D, Goodnough H, Bishop J, Gardner M, Majeti R, Wan DC, Goodman S, Weissman IL, Chang HY, Longaker MT (2018) Identification of the human skeletal stem cell. Cell 175:43–56.e21. https://doi.org/10.1016/j.cell.2018.07.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chase LG, Lakshmipathy U, Solchaga LA, Rao MS, Vemuri MC (2010) A novel serum-free medium for the expansion of human mesenchymal stem cells. Stem Cell Res Ther. https://doi.org/10.1186/scrt8

  • Chen L, Tredget EE, Wu PYG, Wu Y, Wu Y (2008) Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS One 3. https://doi.org/10.1371/journal.pone.0001886

  • Cheng H, Qiu L, Ma J, Zhang H, Cheng M, Li W, Zhao X, Liu K (2011) Replicative senescence of human bone marrow and umbilical cord derived mesenchymal stem cells and their differentiation to adipocytes and osteoblasts. Mol Biol Rep. https://doi.org/10.1007/s11033-010-0665-2

  • Coelho MB, Cabral JMS, Karp JM (2012) Intraoperative stem cell therapy. Annu Rev Biomed Eng 14:325–349. https://doi.org/10.1146/annurev-bioeng-071811-150041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, Andriolo G, Sun B, Zheng B, Zhang L, Norotte C, Teng PN, Traas J, Schugar R, Deasy BM, Badylak S, Buhring HJ, Giacobino JP, Lazzari L, Huard J, Péault B (2008) A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3:301–313. https://doi.org/10.1016/j.stem.2008.07.003

    Article  CAS  PubMed  Google Scholar 

  • Csobonyeiova M, Polak S, Zamborsky R, Danisovic L (2017) iPS cell technologies and their prospect for bone regeneration and disease modeling: a mini review. J Adv Res 8:321

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cui H, Zhu W, Holmes B, Zhang LG (2016) Biologically inspired smart release system based on 3D bioprinted perfused scaffold for vascularized tissue regeneration. Adv Sci. https://doi.org/10.1002/advs.201600058

  • Curtin CM, Tierney EG, Mcsorley K, Cryan SA, Duffy GP, O’Brien FJ (2015) Combinatorial gene therapy accelerates bone regeneration: non-viral dual delivery of VEGF and BMP2 in a collagen-nanohydroxyapatite scaffold. Adv Healthc Mater. https://doi.org/10.1002/adhm.201400397

  • Dalby MJ, Gadegaard N, Oreffo ROC (2014) Harnessing nanotopography and integrin-matrix interactions to influence stem cell fate. Nat Mater. https://doi.org/10.1038/nmat3980

  • Dang M, Saunders L, Niu X, Fan Y, Ma PX (2018) Biomimetic delivery of signals for bone tissue engineering. Bone Res 6:25. https://doi.org/10.1038/s41413-018-0025-8. eCollection 2018.

  • Dawson JI, Kanczler J, Tare R, Kassem M, Oreffo ROC (2014) Concise review: bridging the gap: bone regeneration using skeletal stem cell-based strategies-where are we now? Stem Cells 32:35

    CAS  PubMed  Google Scholar 

  • de Peppo GM, Svensson S, Lennerås M, Synnergren J, Stenberg J, Strehl R, Hyllner J, Thomsen P, Karlsson C (2010) Human embryonic mesodermal progenitors highly resemble human mesenchymal stem cells and display high potential for tissue engineering applications. Tissue Eng Part A 16:2161–2182. https://doi.org/10.1089/ten.TEA.2009.0629

    Article  PubMed  Google Scholar 

  • Di Maggio N, Mehrkens A, Papadimitropoulos A, Schaeren S, Heberer M, Banfi A, Martin I (2012) Fibroblast growth factor-2 maintains a niche-dependent population of self-renewing highly potent non-adherent mesenchymal progenitors through FGFR2c. Stem Cells 30:1455–1464. https://doi.org/10.1002/stem.1106

    Article  CAS  PubMed  Google Scholar 

  • Ding L, Saunders TL, Enikolopov G, Morrison SJ (2012) Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481:457–462. https://doi.org/10.1038/nature10783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (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

    Article  CAS  PubMed  Google Scholar 

  • Dunavin N, Dias A, Li M, McGuirk J (2017) Mesenchymal stromal cells: what is the mechanism in acute graft-versus-host disease? Biomedicine 5:39

    Google Scholar 

  • Einhorn TA, Gerstenfeld LC (2015) Fracture healing: mechanisms and interventions. Nat Rev Rheumatol 11:45–54

    PubMed  Google Scholar 

  • Elgaz S, Kuçi Z, Kuçi S, Bönig H, Bader P (2019) Clinical use of mesenchymal stromal cells in the treatment of acute graft-versus-host disease. Transfus Med Hemother 46:27–34. https://doi.org/10.1159/000496809

    Article  PubMed  PubMed Central  Google Scholar 

  • Emadedin M, Labibzadeh N, Fazeli R, Mohseni F, Hosseini SE, Moghadasali R, Mardpour S, Azimian V, Goodarzi A, Liastani MG, Bafghi AM, Eslaminejad MB, Aghdami N (2017) Percutaneous autologous bone marrow-derived mesenchymal stromal cell implantation is safe for reconstruction of human lower limb long bone atrophic nonunion. Cell J. https://doi.org/10.22074/cellj.2016.4866

  • Emadedin M, Karimi S, Karimi A, Labibzadeh N, Niknejadi M, Baharvand HAN (2019) Autologous bone marrow–derived CD133 cells with core decompression as a novel treatment method for femoral head osteonecrosis: a pilot study. Cytotherapy. https://doi.org/10.1016/j.jcyt.2018.10.005

  • Fedorovich NE, Haverslag RT, Dhert WJA, Alblas J (2010) The role of endothelial progenitor cells in prevascularized bone tissue engineering: development of heterogeneous constructs. Tissue Eng Part A. https://doi.org/10.1089/ten.tea.2009.0603

  • Fedorovich NE, Alblas J, Hennink WE, Öner FC, Dhert WJA (2011) Organ printing: the future of bone regeneration? Trends Biotechnol 29:601–606

    CAS  PubMed  Google Scholar 

  • Feil S, Valtcheva N, Feil R (2009) Inducible cre mice. Methods Mol Biol. https://doi.org/10.1007/978-1-59745-471-1_18

  • Fekete N, Rojewski MT, Fürst D, Kreja L, Ignatius A, Dausend J, Schrezenmeier H (2012) GMP-compliant isolation and large-scale expansion of bone marrow-derived MSC. PLoS One. https://doi.org/10.1371/journal.pone.0043255

  • Fernandez-Yague MA, Abbah SA, McNamara L, Zeugolis DI, Pandit A, Biggs MJ (2015) Biomimetic approaches in bone tissue engineering: integrating biological and physicomechanical strategies. Adv Drug Deliv Rev

    Google Scholar 

  • Frank O, Heim M, Jakob M, Barbero A, Schäfer D, Bendik I, Dick W, Heberer M, Martin I (2002) Real-time quantitative RT-PCR analysis of human bone marrow stromal cells during osteogenic differentiation in vitro. J Cell Biochem 85:737–746. https://doi.org/10.1002/jcb.10174

    Article  CAS  PubMed  Google Scholar 

  • Friedenstein AJ, Chailakhjan RK, Lalykina KS (1970) The development of fibroblast colonies in monolayer cultures of guinea pig bone marrow and spleen cells. Cell Prolif 3:393–403. https://doi.org/10.1111/j.1365-2184.1970.tb00347.x

    Article  CAS  Google Scholar 

  • Frohlich M, Grayson W, Wan L, Marolt D, Drobnic M, Vunjak-Novakovic G (2008) Tissue engineered bone grafts: biological requirements, tissue culture and clinical relevance. Curr Stem Cell Res Ther. https://doi.org/10.2174/157488808786733962

  • Gao F, Chiu SM, Motan DAL, Zhang Z, Chen L, Ji HL, Tse HF, Fu QL, Lian Q (2016) Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis 7. https://doi.org/10.1038/cddis.2015.327

  • García Quiroz F, Posada Estefan O, Gallego Pérez D, Higuita Castro N, Sarassa Velásquez C, Hansford D, Agudelo Florez P, López Rojas L (2008) Isolation of human bone marrow mesenchymal stem cells and evaluation of their osteogenic potential. Rev Ing Bioméd. https://doi.org/10.24050/19099762.n3.2008.43

  • Gibbs DMR, Vaezi M, Yang S, Oreffo ROC (2014) Hope versus hype: what can additive manufacturing realistically offer trauma and orthopedic surgery? Regen Med 9:535

    CAS  PubMed  Google Scholar 

  • Gibon E, Lu L, Goodman SB (2016) Aging, inflammation, stem cells, and bone healing. Stem Cell Res Ther 7:44

    PubMed  Google Scholar 

  • Gimble JM, Katz AJ, Bunnell BA (2007) Adipose-derived stem cells for regenerative medicine. Circ Res 100:1249–1260

    CAS  PubMed  Google Scholar 

  • Gjerde C, Mustafa K, Hellem S, Rojewski M, Gjengedal H, Yassin MA, Feng X, Skaale S, Berge T, Rosen A, Shi XQ, Ahmed AB, Gjertsen BT, Schrezenmeier H, Layrolle P (2018) Cell therapy induced regeneration of severely atrophied mandibular bone in a clinical trial. Stem Cell Res Ther. https://doi.org/10.1186/s13287-018-0951-9

  • Glenn JD (2014) Mesenchymal stem cells: emerging mechanisms of immunomodulation and therapy. World J Stem Cells 6:526. https://doi.org/10.4252/wjsc.v6.i5.526

    Article  PubMed  Google Scholar 

  • Goggin PM, Zygalakis KC, Oreffo ROC, Schneider P (2016) High-resolution 3D imaging of osteocytes and computational modelling in mechanobiology: insights on bone development, ageing, health and disease. Eur Cells Mater. https://doi.org/10.22203/eCM.v031a18

  • Gómez-Barrena E, Rosset P, Gebhard F, Hernigou P, Baldini N, Rouard H, Sensebé L, Gonzalo-Daganzo RM, Giordano R, Padilla-Eguiluz N, García-Rey E, Cordero-Ampuero J, Rubio-Suárez JC, Stanovici J, Ehrnthaller C, Huber-Lang M, Flouzat-Lachaniette CH, Chevallier N, Donati DM, Ciapetti G, Fleury S, Fernandez MN, Cabrera JR, Avendaño-Solá C, Montemurro T, Panaitescu C, Veronesi E, Rojewski MT, Lotfi R, Dominici M, Schrezenmeier H, Layrolle P (2019) Feasibility and safety of treating non-unions in tibia, femur and humerus with autologous, expanded, bone marrow-derived mesenchymal stromal cells associated with biphasic calcium phosphate biomaterials in a multicentric, non-comparative trial. Biomaterials. https://doi.org/10.1016/j.biomaterials.2018.03.033

  • Gothard D, Smith EL, Kanczler JM, Rashidi H, Qutachi O, Henstock J, Rotherham M, El Haj A, Shakesheff KM, Oreffo ROC (2014) Tissue engineered bone using select growth factors: a comprehensive review of animal studies and clinical translation studies in man. Eur Cells Mater. https://doi.org/10.22203/eCM.v028a13

  • Granero-Moltó F, Weis JA, Miga MI, Landis B, Myers TJ, O’Rear L, Longobardi L, Jansen ED, Mortlock DP, Spagnoli A (2009) Regenerative effects of transplanted mesenchymal stem cells in fracture healing. Stem Cells. https://doi.org/10.1002/stem.103

  • Grayson WL, Fröhlich M, Yeager K, Bhumiratana S, Chan ME, Cannizzaro C, Wan LQ, Liu XS, Guo XE, Vunjak-Novakovic G (2010) Engineering anatomically shaped human bone grafts. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.0905439106

  • Grayson WL, Marolt D, Bhumiratana S, Fröhlich M, Guo XE, Vunjak-Novakovic G (2011) Optimizing the medium perfusion rate in bone tissue engineering bioreactors. Biotechnol Bioeng. https://doi.org/10.1002/bit.23024

  • Grcevic D, Pejda S, Matthews BG, Repic D, Wang L, Li H, Kronenberg MS, Jiang X, Maye P, Adams DJ, Rowe DW, Aguila HL, Kalajzic I (2012) In vivo fate mapping identifies mesenchymal progenitor cells. Stem Cells 30:187–196. https://doi.org/10.1002/stem.780

    Article  CAS  PubMed  Google Scholar 

  • Grisendi G, Annerén C, Cafarelli L, Sternieri R, Veronesi E, Cervo GL, Luminari S, Maur M, Frassoldati A, Palazzi G, Otsuru S, Bambi F, Paolucci P, Pierfranco C, Horwitz E, Dominici M (2010) GMP-manufactured density gradient media for optimized mesenchymal stromal/stem cell isolation and expansion. Cytotherapy 12:466–477. https://doi.org/10.3109/14653241003649510

    Article  CAS  PubMed  Google Scholar 

  • Guo Z, Li H, Li X, Yu X, Wang H, Tang P, Mao N (2006) In vitro characteristics and in vivo immunosuppressive activity of compact bone-derived murine mesenchymal progenitor cells. Stem Cells 24:992–1000. https://doi.org/10.1634/stemcells.2005-0224

    Article  PubMed  Google Scholar 

  • Harrell CR, Markovic BS, Fellabaum C, Arsenijevic A, Volarevic V (2019) Mesenchymal stem cell-based therapy of osteoarthritis: current knowledge and future perspectives. Biomed Pharmacother 109:2318

    CAS  PubMed  Google Scholar 

  • Haumer A, Bourgine PE, Occhetta P, Born G, Tasso R, Martin I (2018) Delivery of cellular factors to regulate bone healing. Adv Drug Deliv Rev 129:285

    CAS  PubMed  Google Scholar 

  • Hauzeur JP, De Maertelaer V, Baudoux E, Malaise M, Beguin Y, Gangji V (2018) Inefficacy of autologous bone marrow concentrate in stage three osteonecrosis: a randomized controlled double-blind trial. Int Orthop. https://doi.org/10.1007/s00264-017-3650-8

  • Hernigou P, Beaujean F (2002) Treatment of osteonecrosis with autologous bone marrow grafting. In: Clinical Orthopaedics and related research. Lippincott Williams & Wilkins, Hagerstown

    Google Scholar 

  • Hernigou P, Poignard A, Beaujean F, Rouard H (2005) Percutaneous autologous bone-marrow grafting for nonunions: influence of the number and concentration of progenitor cells. J Bone Jt Surg A. https://doi.org/10.2106/JBJS.D.02215

  • Hernigou P, Homma Y, Flouzat Lachaniette CH, Poignard A, Allain J, Chevallier N, Rouard H (2013) Benefits of small volume and small syringe for bone marrow aspirations of mesenchymal stem cells. Int Orthop 37:2279–2287. https://doi.org/10.1007/s00264-013-2017-z

    Article  PubMed  Google Scholar 

  • Hernigou P, Dubory A, Homma Y, Guissou I, Flouzat Lachaniette CH, Chevallier N, Rouard H (2018) Cell therapy versus simultaneous contralateral decompression in symptomatic corticosteroid osteonecrosis: a thirty year follow-up prospective randomized study of one hundred and twenty five adult patients. Int Orthop. https://doi.org/10.1007/s00264-018-3941-8

  • Herrmann M, Hildebrand M, Menzel U, Fahy N, Alini M, Lang S, Benneker L, Verrier S, Stoddart MJ, Bara JJ (2019) Phenotypic characterization of bone marrow mononuclear cells and derived stromal cell populations from human iliac crest, vertebral body and femoral head. Int J Mol Sci. https://doi.org/10.3390/ijms20143454

  • Hofer HR, Tuan RS (2016) Secreted trophic factors of mesenchymal stem cells support neurovascular and musculoskeletal therapies. Stem Cell Res Ther 7:1–14. https://doi.org/10.1186/s13287-016-0394-0

    Article  CAS  Google Scholar 

  • Hofmann S, Hagenmüller H, Koch AM, Müller R, Vunjak-Novakovic G, Kaplan DL, Merkle HP, Meinel L (2007) Control of in vitro tissue-engineered bone-like structures using human mesenchymal stem cells and porous silk scaffolds. Biomaterials. https://doi.org/10.1016/j.biomaterials.2006.10.019

  • Ho-Shui-Ling A, Bolander J, Rustom LE, Johnson AW, Luyten FP, Picart C (2018) Bone regeneration strategies: engineered scaffolds, bioactive molecules and stem cells current stage and future perspectives. Biomaterials 180:143

    CAS  PubMed  Google Scholar 

  • Houlihan DD, Mabuchi Y, Morikawa S, Niibe K, Araki D, Suzuki S, Okano H, Matsuzaki Y (2012) Isolation of mouse mesenchymal stem cells on the basis of expression of Sca-1 and PDGFR-α. Nat Protoc 7:2103–2111. https://doi.org/10.1038/nprot.2012.125

    Article  CAS  PubMed  Google Scholar 

  • Hung BP, Hutton DL, Kozielski KL, Bishop CJ, Naved B, Green JJ, Caplan AI, Gimble JM, Dorafshar AH, Grayson WL (2015) Platelet-derived growth factor BB enhances Osteogenesis of adipose-derived but not bone marrow-derived mesenchymal stromal/stem cells. Stem Cells 33:2773–2784. https://doi.org/10.1002/stem.2060

    Article  CAS  PubMed  Google Scholar 

  • Ikebe C, Suzuki K (2014) Mesenchymal stem cells for regenerative therapy: optimization of cell preparation protocols. Biomed Res Int 2014:1–11. https://doi.org/10.1155/2014/951512

    Article  Google Scholar 

  • 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. https://doi.org/10.1002/(SICI)1097-4644(199702)64:2<295::AID-JCB12>3.0.CO;2-I

    Article  CAS  PubMed  Google Scholar 

  • Johnstone B, Hering TM, Caplan AI, Goldberg VM, Yoo JU (1998) In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells. Exp Cell Res 238:265–272. https://doi.org/10.1006/excr.1997.3858

    Article  CAS  PubMed  Google Scholar 

  • Jones E, McGonagle D (2008) Human bone marrow mesenchymal stem cells in vivo. Rheumatology 47:126–131. https://doi.org/10.1093/rheumatology/kem206

    Article  CAS  PubMed  Google Scholar 

  • Jones E, English A, Churchman SM, Kouroupis D, Boxall SA, Kinsey S, Giannoudis PG, Emery P, McGonagle D (2010) Large-scale extraction and characterization of CD271+ multipotential stromal cells from trabecular bone in health and osteoarthritis: implications for bone regeneration strategies based on uncultured or minimally cultured multipotential stromal cells. Arthritis Rheum 62:1944–1954. https://doi.org/10.1002/art.27451

    Article  CAS  PubMed  Google Scholar 

  • Juhl M, Tratwal J, Follin B, Søndergaard RH, Kirchhoff M, Ekblond A, Kastrup J, Haack-Sørensen M (2016) Comparison of clinical grade human platelet lysates for cultivation of mesenchymal stromal cells from bone marrow and adipose tissue. Scand J Clin Lab Invest. https://doi.org/10.3109/00365513.2015.1099723

  • Kanczler JM, Oreffo ROC (2008) Osteogenesis and angiogenesis: the potential for engineering bone. Eur Cell Mater 15:100

    CAS  PubMed  Google Scholar 

  • Kandal S, Özmen S, Uygur S, Yagci M, Kayhan H, Elmas C, Araç M, Çelebi C (2016) Effects of rat bone marrow-derived mesenchymal stem cells and demineralized bone matrix on cranial bone healing. Ann Plast Surg 77:249–254. https://doi.org/10.1097/SAP.0000000000000274

    Article  CAS  PubMed  Google Scholar 

  • Kang HW, Lee SJ, Ko IK, Kengla C, Yoo JJ, Atala A (2016) A 3D bioprinting system to produce human-scale tissue constructs with structural integrity. Nat Biotechnol. https://doi.org/10.1038/nbt.3413

  • Kang J, Zhang L, Luo X, Ma X, Wang G, Yang Y, Yan Y, Qian H, Zhang X, Xu W, Mao F (2018) Systematic exposition of mesenchymal stem cell for inflammatory bowel disease and its associated colorectal cancer. Biomed Res Int 2018:1

    Google Scholar 

  • Kawaguchi H, Hirachi A, Hasegawa N, Iwata T, Hamaguchi H, Shiba H, Takata T, Kato Y, Kurihara H (2004) Enhancement of periodontal tissue regeneration by transplantation of bone marrow mesenchymal stem cells. J Periodontol. https://doi.org/10.1902/jop.2004.75.9.1281

  • Keriquel V, Oliveira H, Rémy M, Ziane S, Delmond S, Rousseau B, Rey S, Catros S, Amédée J, Guillemot F, Fricain JC (2017) In situ printing of mesenchymal stromal cells, by laser-assisted bioprinting, for in vivo bone regeneration applications. Sci Rep. https://doi.org/10.1038/s41598-017-01914-x

  • Kesireddy V, Kasper FK (2016) Approaches for building bioactive elements into synthetic scaffolds for bone tissue engineering. J Mater Chem B 4:6773

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kim BS, Shkembi F, Lee J (2017) In vitro and in vivo evaluation of commercially available fibrin gel as a carrier of alendronate for bone tissue engineering. Biomed Res Int. https://doi.org/10.1155/2017/6434169

  • Kim H, Kim M, Im S-K, Fang S (2018) Mouse Cre-LoxP system: general principles to determine tissue-specific roles of target genes. Lab Anim Res 34:147–159. https://doi.org/10.5625/lar.2018.34.4.147

    Article  PubMed  PubMed Central  Google Scholar 

  • Ko E, Alberti K, Lee JS, Yang K, Jin Y, Shin J, Yang HS, Xu Q, Cho S-W (2016) Nanostructured tendon-derived scaffolds for enhanced bone regeneration by human adipose-derived stem cells. ACS Appl Mater Interfaces 8:22819–22829. https://doi.org/10.1021/acsami.6b05358

    Article  CAS  PubMed  Google Scholar 

  • Kobolak J, Dinnyes A, Memic A, Khademhosseini A, Mobasheri A (2016) Mesenchymal stem cells: identification, phenotypic characterization, biological properties and potential for regenerative medicine through biomaterial micro-engineering of their niche. Methods 99:62–68

    CAS  PubMed  Google Scholar 

  • Kolesky DB, Truby RL, Gladman AS, Busbee TA, Homan KA, Lewis JA (2014) 3D bioprinting of vascularized, heterogeneous cell-laden tissue constructs. Adv Mater. https://doi.org/10.1002/adma.201305506

  • Koons GL, Mikos AG (2019) Progress in three-dimensional printing with growth factors. J Control Release. https://doi.org/10.1016/j.jconrel.2018.12.035

  • Krampera M, Cosmi L, Angeli R, Pasini A, Liotta F, Andreini A, Santarlasci V, Mazzinghi B, Pizzolo G, Vinante F, Romagnani P, Maggi E, Romagnani S, Annunziato F (2006) Role for interferon-γ in the Immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 24:386–398. https://doi.org/10.1634/stemcells.2005-0008

    Article  CAS  PubMed  Google Scholar 

  • Kristjánsson B, Honsawek S (2014) Current perspectives in mesenchymal stem cell therapies for osteoarthritis. Stem Cells Int 2014:1

    Google Scholar 

  • Kumar R, Godavarthy PS, Krause DS (2018) The bone marrow microenvironment in health and disease at a glance. J Cell Sci 131:jcs201707. https://doi.org/10.1242/jcs.201707

    Article  CAS  PubMed  Google Scholar 

  • Kunisaki Y, Bruns I, Scheiermann C, Ahmed J, Pinho S, Zhang D, Mizoguchi T, Wei Q, Lucas D, Ito K, Mar JC, Bergman A, Frenette PS (2013) Arteriolar niches maintain haematopoietic stem cell quiescence. Nature 502:637–643. https://doi.org/10.1038/nature12612

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lai Y, Sun Y, Skinner CM, Son EL, Lu Z, Tuan RS, Jilka RL, Ling J, Chen XD (2010) Reconstitution of marrow-derived extracellular matrix ex vivo: a robust culture system for expanding large-scale highly functional human mesenchymal stem cells. Stem Cells Dev 19:1095–1107. https://doi.org/10.1089/scd.2009.0217

    Article  CAS  PubMed  Google Scholar 

  • Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringdén O (2003) Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and Mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 57:11–20. https://doi.org/10.1046/j.1365-3083.2003.01176.x

    Article  PubMed  Google Scholar 

  • Le Nail LR, Stanovici J, Fournier J, Splingard M, Domenech J, Rosset P (2014) Percutaneous grafting with bone marrow autologous concentrate for open tibia fractures: analysis of forty three cases and literature review. Int Orthop. https://doi.org/10.1007/s00264-014-2342-x

  • Lee H-S, Huang G-T, Chiang H, Chiou L-L, Chen M-H, Hsieh C-H, Jiang C-C (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

    Article  CAS  PubMed  Google Scholar 

  • Leijten J, Chai YC, Papantoniou I, Geris L, Schrooten J, Luyten FP (2015) Cell based advanced therapeutic medicinal products for bone repair: keep it simple? Adv Drug Deliv Rev 84:30

    CAS  PubMed  Google Scholar 

  • Léotot J, Lebouvier A, Hernigou P, Bierling P, Rouard H, Chevallier N (2015) Bone-forming capacity and biodistribution of bone marrow-derived stromal cells directly loaded into scaffolds: a novel and easy approach for clinical application of bone regeneration. Cell Transplant. https://doi.org/10.3727/096368914X685276

  • Li WJ, Tuli R, Okafor C, Derfoul A, Danielson KG, Hall DJ, Tuan RS (2005) A three-dimensional nanofibrous scaffold for cartilage tissue engineering using human mesenchymal stem cells. Biomaterials 26:599–609. https://doi.org/10.1016/j.biomaterials.2004.03.005

    Article  CAS  PubMed  Google Scholar 

  • Li B, Menzel U, Loebel C, Schmal H, Alini M, Stoddart MJ (2016) Monitoring live human mesenchymal stromal cell differentiation and subsequent selection using fluorescent RNA-based probes. Sci Rep. https://doi.org/10.1038/srep26014

  • Liebergall M, Schroeder J, Mosheiff R, Gazit Z, Yoram Z, Rasooly L, Daskal A, Khoury A, Weil Y, Beyth S (2013) Stem cell-based therapy for prevention of delayed fracture union: a randomized and prospective preliminary study. Mol Ther. https://doi.org/10.1038/mt.2013.109

  • Liu Y, Teoh SH, Chong MSK, Yeow CH, Kamm RD, Choolani M, Chan JKY (2013) Contrasting effects of vasculogenic induction upon biaxial bioreactor stimulation of mesenchymal stem cells and endothelial progenitor cells cocultures in three-dimensional scaffolds under in vitro and in vivo paradigms for vascularized bone tissue engine. Tissue Eng Part A. https://doi.org/10.1089/ten.tea.2012.0187

  • Liu Y, Chan JKY, Teoh SH (2015) Review of vascularised bone tissue-engineering strategies with a focus on co-culture systems. J Tissue Eng Regen Med 9:85

    CAS  PubMed  Google Scholar 

  • Lode A, Bernhardt A, Gelinsky M (2008) Cultivation of human bone marrow stromal cells on three-dimensional scaffolds of mineralized collagen: influence of seeding density on colonization, proliferation and osteogenic differentiation. J Tissue Eng Regen Med. https://doi.org/10.1002/term.110

  • Loi F, Córdova LA, Pajarinen J, Lin T, Yao Z, Goodman SB (2016) Inflammation, fracture and bone repair. Bone 86:119

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ma J, Both SK, Yang F, Cui F-Z, Pan J, Meijer GJ, Jansen JA, van den Beucken JJJP (2014) Concise review: cell-based strategies in bone tissue engineering and regenerative medicine. Stem Cells Transl Med. https://doi.org/10.5966/sctm.2013-0126

  • Marolt Presen D, Traweger A, Gimona M, Redl H (2019) Mesenchymal stromal cell-based bone regeneration therapies: from cell transplantation and tissue engineering to therapeutic Secretomes and extracellular vesicles. Front Bioeng Biotechnol 7:1–20. https://doi.org/10.3389/fbioe.2019.00352

    Article  Google Scholar 

  • Marolt D, Augst A, Freed LE, Vepari C, Fajardo R, Patel N, Gray M, Farley M, Kaplan D, Vunjak-Novakovic G (2006) Bone and cartilage tissue constructs grown using human bone marrow stromal cells, silk scaffolds and rotating bioreactors. Biomaterials 27:6138–6149. https://doi.org/10.1016/j.biomaterials.2006.07.015

    Article  CAS  PubMed  Google Scholar 

  • Martin I, Muraglia A, Campanile G, Cancedda R, Quarto R (1997) Fibroblast growth factor-2 supports ex vivo expansion and maintenance of osteogenic precursors from human bone marrow. Endocrinology 138:4456–4462. https://doi.org/10.1210/endo.138.10.5425

    Article  CAS  PubMed  Google Scholar 

  • Mauney JR, Volloch V, Kaplan DL (2005) Matrix-mediated retention of adipogenic differentiation potential by human adult bone marrow-derived mesenchymal stem cells during ex vivo expansion. Biomaterials 26:6167–6175. https://doi.org/10.1016/j.biomaterials.2005.03.024

    Article  CAS  PubMed  Google Scholar 

  • Mauney JR, Kirker-Head C, Abrahamson L, Gronowicz G, Volloch V, Kaplan DL (2006) Matrix-mediated retention of in vitro osteogenic differentiation potential and in vivo bone-forming capacity by human adult bone marrow-derived mesenchymal stem cells during ex vivo expansion. J Biomed Mater Res Part A 79:464–475. https://doi.org/10.1002/jbm.a.30876

    Article  CAS  Google Scholar 

  • McBeath R, Pirone DM, Nelson CM, Bhadriraju K, Chen CS (2004) Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev Cell 6:483–495

    CAS  PubMed  Google Scholar 

  • Melchels FPW, Domingos MAN, Klein TJ, Malda J, Bartolo PJ, Hutmacher DW (2012) Additive manufacturing of tissues and organs. Prog Polym Sci 37:1079

    CAS  Google Scholar 

  • Melke J, Zhao F, Ito K, Hofmann S (2020) Orbital seeding of mesenchymal stromal cells increases osteogenic differentiation and bone-like tissue formation. J Orthop Res. https://doi.org/10.1002/jor.24583

  • Méndez-Ferrer S, Michurina TV, Ferraro F, Mazloom AR, MacArthur BD, Lira SA, Scadden DT, Ma’ayan A, Enikolopov GN, Frenette PS (2010) Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466:829–834. https://doi.org/10.1038/nature09262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mendicino M, Bailey AM, Wonnacott K, Puri RK, Bauer SR (2014) MSC-based product characterization for clinical trials: an FDA perspective. Cell Stem Cell 14:141–145

    CAS  PubMed  Google Scholar 

  • Miao C, Lei M, Hu W, Han S, Wang Q (2017) A brief review: the therapeutic potential of bone marrow mesenchymal stem cells in myocardial infarction. Stem Cell Res Ther 8:242

    PubMed  PubMed Central  Google Scholar 

  • Mizoguchi T, Pinho S, Ahmed J, Kunisaki Y, Hanoun M, Mendelson A (2014) Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development. Dev Cell 29:340

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mizuhashi K, Ono W, Matsushita Y, Sakagami N, Takahashi A, Saunders TL, Nagasawa T, Kronenberg HM, Ono N (2018) Resting zone of the growth plate houses a unique class of skeletal stem cells. Nature. https://doi.org/10.1038/s41586-018-0662-5

  • Morikawa S, Mabuchi Y, Kubota Y, Nagai Y, Niibe K, Hiratsu E, Suzuki S, Miyauchi-Hara C, Nagoshi N, Sunabori T, Shimmura S, Miyawaki A, Nakagawa T, Suda T, Okano H, Matsuzaki Y (2009) Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow. J Exp Med 206:2483–2496. https://doi.org/10.1084/jem.20091046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murgia A, Veronesi E, Candini O, Caselli A, D’Souza N, Rasini V, Giorgini A, Catani F, Iughetti L, Dominici M, Burns JS (2016) Potency biomarker signature genes from multiparametric osteogenesis assays: will cGMP human bone marrow mesenchymal stromal cells make bone? PLoS One. https://doi.org/10.1371/journal.pone.0163629

  • Murphy JM, Dixon K, Beck S, Fabian D, Feldman A, Barry F (2002) Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis. Arthritis Rheum 46:704–713. https://doi.org/10.1002/art.10118

    Article  PubMed  Google Scholar 

  • Muschler GF, Boehm C, Easley K (1997) Aspiration to obtain osteoblast progenitor cells from human bone marrow: the influence of aspiration volume. J Bone Jt Surg A 79:1699–1709. https://doi.org/10.2106/00004623-199711000-00012

    Article  CAS  Google Scholar 

  • Nakamura A, Akahane M, Shigematsu H, Tadokoro M, Morita Y, Ohgushi H, Dohi Y, Imamura T, Tanaka Y (2010) Cell sheet transplantation of cultured mesenchymal stem cells enhances bone formation in a rat nonunion model. Bone. https://doi.org/10.1016/j.bone.2009.08.048

  • Nguyen LH, Annabi N, Nikkhah M, Bae H, Binan L, Park S, Kang Y, Yang Y, Khademhosseini A (2012) Vascularized bone tissue engineering: approaches for potential improvement. Tissue Eng Part B Rev. https://doi.org/10.1089/ten.teb.2012.0012

  • Omatsu Y, Sugiyama T, Kohara H, Kondoh G, Fujii N, Kohno K, Nagasawa T (2010) The essential functions of Adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity 33:387–399. https://doi.org/10.1016/J.IMMUNI.2010.08.017

    Article  CAS  PubMed  Google Scholar 

  • Ono N, Ono W, Mizoguchi T, Nagasawa T, Frenette PS, Kronenberg HM (2014a) Vasculature-associated cells expressing nestin in developing bones encompass early cells in the osteoblast and endothelial lineage. Dev Cell 29:330–339. https://doi.org/10.1016/j.devcel.2014.03.014

    Article  CAS  PubMed  Google Scholar 

  • Ono N, Ono W, Nagasawa T, Kronenberg HM (2014b) A subset of chondrogenic cells provides early mesenchymal progenitors in growing bones. Nat Cell Biol 16:1157–1167. https://doi.org/10.1038/ncb3067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Oryan A, Alidadi S, Moshiri A, Maffulli N (2014) Bone regenerative medicine: classic options, novel strategies, and future directions. J Orthop Surg Res 9:18

    PubMed  Google Scholar 

  • Oryan A, Kamali A, Moshirib A, Eslaminejad MB (2017) Role of mesenchymal stem cells in bone regenerative medicine: what is the evidence? Cells Tissues Organs 204:59–83. https://doi.org/10.1159/000469704

    Article  CAS  PubMed  Google Scholar 

  • Park D, Spencer JA, Koh BI, Kobayashi T, Fujisaki J, Clemens TL, Lin CP, Kronenberg HM, Scadden DT (2012) Cell stem cell endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Stem Cell 10:259–272. https://doi.org/10.1016/j.stem.2012.02.003

    Article  CAS  Google Scholar 

  • Petite H, Viateau V, Bensaïd W, Meunier A, De Pollak C, Bourguignon M, Oudina K, Sedel L, Guillemin G (2000) Tissue-engineered bone regeneration. Nat Biotechnol. https://doi.org/10.1038/79449

  • Pineault KM, Song JY, Kozloff KM, Lucas D, Wellik DM (2019) Hox11 expressing regional skeletal stem cells are progenitors for osteoblasts, chondrocytes and adipocytes throughout life. Nat Commun 10. https://doi.org/10.1038/s41467-019-11100-4

  • Pinho S, Lacombe J, Hanoun M, Mizoguchi T, Bruns I, Kunisaki Y, Frenette PS (2013) PDGFRα and CD51 mark human nestin+ sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion. J Exp Med 210:1351–1367. https://doi.org/10.1084/jem.20122252

    Article  CAS  PubMed  Google Scholar 

  • Pittenger M, Mackay A, Beck S, Jaiswal R, Douglas R, Mosca J, Moorman M, Simonetti D, Craig S, Marshak D (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147. https://doi.org/10.1126/science.284.5411.143

    Article  CAS  PubMed  Google Scholar 

  • Ponte AL, Marais E, Gallay N, Langonné A, Delorme B, Hérault O, Charbord P, Domenech J (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

    Article  CAS  PubMed  Google Scholar 

  • Pountos I, Corscadden D, Emery P, Giannoudis PV (2007) Mesenchymal stem cell tissue engineering: techniques for isolation, expansion and application. Injury 38(Suppl 4):S23–S33. https://doi.org/10.1016/s0020-1383(08)70006-8

    Article  PubMed  Google Scholar 

  • Quarto R, Mastrogiacomo M, Cancedda R, Kutepov SM, Mukhachev V, Lavroukov A, Kon E, Marcacci M (2001) Repair of large bone defects with the use of autologous bone marrow stromal cells. N Engl J Med 344:385. https://doi.org/10.1056/NEJM200102013440516

  • Raftery RM, Mencía-Castaño I, Sperger S, Chen G, Cavanagh B, Feichtinger GA, Redl H, Hacobian A, O’Brien FJ (2018) Delivery of the improved BMP-2-advanced plasmid DNA within a gene-activated scaffold accelerates mesenchymal stem cell osteogenesis and critical size defect repair. J Control Release. https://doi.org/10.1016/j.jconrel.2018.05.022

  • Redondo LM, García V, Peral B, Verrier A, Becerra J, Sánchez A, García-Sancho J (2018) Repair of maxillary cystic bone defects with mesenchymal stem cells seeded on a cross-linked serum scaffold. J Cranio-Maxillofac Surg. https://doi.org/10.1016/j.jcms.2017.11.004

  • Regulski MJ (2017) Mesenchymal stem cells: “Guardians of inflammation”. Wounds 29:20–27

    PubMed  Google Scholar 

  • Reinisch A, Etchart N, Thomas D, Hofmann NA, Fruehwirth M, Sinha S, Chan CK, Senarath-Yapa K, Seo EY, Wearda T, Hartwig UF, Beham-Schmid C, Trajanoski S, Lin Q, Wagner W, Dullin C, Alves F, Andreeff M, Weissman IL, Longaker MT, Schallmoser K, Majeti R, Strunk D (2015) Epigenetic and in vivo comparison of diverse MSC sources reveals an endochondral signature for human hematopoietic niche formation. Blood 125:249–260. https://doi.org/10.1182/blood-2014-04-572255

    Article  CAS  PubMed  Google Scholar 

  • Robey PG, Kuznetsov SA, Ren J, Klein HG, Sabatino M, Stroncek DF (2015) Generation of clinical grade human bone marrow stromal cells for use in bone regeneration. Bone. https://doi.org/10.1016/j.bone.2014.07.020

  • Roelofs AJ, Zupan J, Riemen AHK, Kania K, Ansboro S, White N, Clark SM, De Bari C (2017) Joint morphogenetic cells in the adult mammalian synovium. Nat Commun 8:15040. https://doi.org/10.1038/ncomms15040

    Article  CAS  PubMed  Google Scholar 

  • Rosen CJ, Bouillon R, Compston JE, Rosen V (2013) Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 8th Edition. ISBN: 978-1-118-45388-9. https://www.wiley.com/en-us/Primer+on+the+Metabolic+Bone+Diseases+and+Disorders+of+Mineral+Metabolism%2C+8th+Edition-p-9781118453889

  • Rosen CJ, Bouxsein ML (2006) Mechanisms of disease: is osteoporosis the obesity of bone? Nat Clin Pract Rheumatol 2:35–43. https://doi.org/10.1038/ncprheum0070

    Article  CAS  PubMed  Google Scholar 

  • Roseti L, Parisi V, Petretta M, Cavallo C, Desando G, Bartolotti I, Grigolo B (2017) Scaffolds for bone tissue engineering: state of the art and new perspectives. Mater Sci Eng C 78:1246

    CAS  Google Scholar 

  • Sacchetti B, Funari A, Michienzi S, Di Cesare S, Piersanti S, Saggio I, Tagliafico E, Ferrari S, Robey PG, Riminucci M, Bianco P (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

    Article  CAS  PubMed  Google Scholar 

  • Sacchetti B, Funari A, Remoli C, Giannicola G, Kogler G, Liedtke S, Cossu G, Serafini M, Sampaolesi M, Tagliafico E, Tenedini E, Saggio I, Robey PG, Riminucci M, Bianco P (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

    Article  CAS  Google Scholar 

  • Sakaguchi Y, Sekiya I, Yagishita K, Ichinose S, Shinomiya K, Muneta T (2009) Suspended cells from trabecular bone by collagenase digestion become virtually identical to mesenchymal stem cells obtained from marrow suspended cells from trabecular bone by collagenase digestion become virtually identical to mesenchymal stem cells obta. Stem Cells 104:2728–2735. https://doi.org/10.1182/blood-2003-12-4452

    Article  CAS  Google Scholar 

  • Samsonraj RM, Rai B, Sathiyanathan P, Puan KJ, Rötzschke O, Hui JH, Raghunath M, Stanton LW, Nurcombe V, Cool SM (2015) Establishing criteria for human mesenchymal stem cell potency. Stem Cells. https://doi.org/10.1002/stem.1982

  • Sanchez-Guijo FM, Blanco JF, Cruz G, Muntion S, Gomez M, Carrancio S, Lopez-Villar O, Barbado MV, Sanchez-Abarca LI, Blanco B, Briñon JG, Del Cañizo MC (2009) Multiparametric comparison of mesenchymal stromal cells obtained from trabecular bone by using a novel isolation method with those obtained by iliac crest aspiration from the same subjects. Cell Tissue Res 336:501–507. https://doi.org/10.1007/s00441-009-0778-x

    Article  PubMed  Google Scholar 

  • Santiesteban DY, Kubelick K, Dhada KS, Dumani D, Suggs L, Emelianov S (2016) Monitoring/imaging and regenerative agents for enhancing tissue engineering characterization and therapies. Ann Biomed Eng 44:750–772. https://doi.org/10.1007/s10439-015-1509-y

    Article  PubMed  Google Scholar 

  • Santo VE, Gomes ME, Mano JF, Reis RL (2013) Controlled release strategies for bone, cartilage, and osteochondral engineering-Part ii: challenges on the evolution from single to multiple bioactive factor delivery. Tissue Eng B Rev 19:327

    CAS  Google Scholar 

  • Schallmoser K, Rohde E, Reinisch A, Bartmann C, Thaler D, Drexler C, Obenauf AC, Lanzer G, Linkesch W, Strunk D (2008) Rapid large-scale expansion of functional mesenchymal stem cells from unmanipulated bone marrow without animal serum. Tissue Eng Part C Methods 14:185–196. https://doi.org/10.1089/ten.tec.2008.0060

    Article  CAS  PubMed  Google Scholar 

  • Schallmoser K, Bartmann C, Rohde E, Bork S, Guelly C, Obenauf AC, Reinisch A, Horn P, Ho AD, Strunk D, Wagner W (2010) Replicative senescence-associated gene expression changes in mesenchymal stromal cells are similar under different culture conditions. Haematologica 95:867–874. https://doi.org/10.3324/haematol.2009.011692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sensebé 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

    PubMed  Google Scholar 

  • Siddiqui JA, Partridge NC (2016) Physiological bone remodeling: systemic regulation and growth factor involvement. Physiology 31:233

    CAS  PubMed  Google Scholar 

  • Sikavitsas VI, Bancroft GN, Holtorf HL, Jansen JA, Mikos AG (2003) Mineralized matrix deposition by marrow stromal osteoblasts in 3D perfusion culture increases with increasing fluid shear forces. Proc Natl Acad Sci USA. https://doi.org/10.1073/pnas.2434367100

  • Solchaga LA, Penick K, Porter JD, Goldberg VM, Caplan AI, Welter JF (2005) FGF-2 enhances the mitotic and chondrogenic potentials of human adult bone marrow-derived mesenchymal stem cells. J Cell Physiol 203:398–409. https://doi.org/10.1002/jcp.20238

    Article  CAS  PubMed  Google Scholar 

  • Solchaga LA, Penick K, Goldberg VM, Caplan AI, Welter JF (2010) Fibroblast growth factor-2 enhances proliferation and delays loss of chondrogenic potential in human adult bone-marrow-derived mesenchymal stem cells. Tissue Eng Part A 16:1009–1019. https://doi.org/10.1089/ten.TEA.2009.0100

    Article  PubMed  Google Scholar 

  • Soriano P (1999) Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet 21:70

    CAS  PubMed  Google Scholar 

  • Stockmann P, Park J, Von Wilmowsky C, Nkenke E, Felszeghy E, Dehner JF, Schmitt C, Tudor C, Schlegel KA (2012) Guided bone regeneration in pig calvarial bone defects using autologous mesenchymal stem/progenitor cells – a comparison of different tissue sources. J Cranio-Maxillofac Surg 40:310–320. https://doi.org/10.1016/j.jcms.2011.05.004

    Article  Google Scholar 

  • Stolzing A, Jones E, McGonagle D, Scutt A (2008) Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech Ageing Dev 129:163–173. https://doi.org/10.1016/j.mad.2007.12.002

    Article  CAS  PubMed  Google Scholar 

  • Sugiyama T, Kohara H, Noda M, Nagasawa T (2006) Maintenance of the hematopoietic stem cell Pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25:977–988. https://doi.org/10.1016/j.immuni.2006.10.016

    Article  CAS  PubMed  Google Scholar 

  • Sukul M, Nguyen TBL, Min YK, Lee SY, Lee BT (2015) Effect of local sustainable release of BMP2-VEGF from Nano-cellulose loaded in sponge biphasic calcium phosphate on bone regeneration. Tissue Eng Part A. https://doi.org/10.1089/ten.tea.2014.0497

  • Szpalski C, Barbaro M, Sagebin F, Warren SM (2012) Bone tissue engineering: current strategies and techniques-Part II: cell types. Tissue Eng Part B Rev 18:258

    CAS  PubMed  Google Scholar 

  • Tang D, Tare RS, Yang LY, Williams DF, Ou KL, Oreffo ROC (2016) Biofabrication of bone tissue: approaches, challenges and translation for bone regeneration. Biomaterials 83:363

    CAS  PubMed  Google Scholar 

  • Tarafder S, Lee CH (2017) 3D printing integrated with controlled delivery for musculoskeletal tissue engineering. J 3D Print Med 1:181–189. https://doi.org/10.2217/3dp-2017-0005

    Article  CAS  Google Scholar 

  • Tasoglu S, Demirci U (2013) Bioprinting for stem cell research. Trends Biotechnol 31:10

    CAS  PubMed  Google Scholar 

  • Tikhonova AN, Dolgalev I, Hu H, Sivaraj KK, Hoxha E, Cuesta-Domínguez Á, Pinho S, Akhmetzyanova I, Gao J, Witkowski M, Guillamot M, Gutkin MC, Zhang Y, Marier C, Diefenbach C, Kousteni S, Heguy A, Zhong H, Fooksman DR, Butler JM, Economides A, Frenette PS, Adams RH, Satija R, Tsirigos A, Aifantis I (2019) The bone marrow microenvironment at single-cell resolution. Nature 569:222–228. https://doi.org/10.1038/s41586-019-1104-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Timmins NE, Scherberich A, Früh JA, Heberer M, Martin I, Jakob M (2007) Three-dimensional cell culture and tissue engineering in a T-CUP (tissue culture under perfusion). Tissue Eng. https://doi.org/10.1089/ten.2006.0158

  • Tuli R, Tuli S, Nandi S, Wang ML, Alexander PG, Haleem-Smith H, Hozack WJ, Manner PA, Danielson KG, Tuan RS (2003) Characterization of multipotential mesenchymal progenitor cells derived from human trabecular bone. Stem Cells 21:681–693. https://doi.org/10.1634/stemcells.21-6-681

    Article  CAS  PubMed  Google Scholar 

  • Turnbull G, Clarke J, Picard F, Riches P, Jia L, Han F, Li B, Shu W (2018) 3D bioactive composite scaffolds for bone tissue engineering. Bioact Mater 3:278

    PubMed  Google Scholar 

  • Uccelli A, Laroni A, Brundin L, Clanet M, Fernandez O, Nabavi SM, Muraro PA, Oliveri RS, Radue EW, Sellner J, Soelberg Sorensen P, Sormani MP, Wuerfel JT, Battaglia MA, Freedman MS, Bonetti B, Rush C, Herrera C, Ramo Tello C, Miller D, Szwajcer D, Strunk D, Wall D, Aguera-Morales E, Rohde E, Dazzi F, Comi G, Martino G, Izquierdo Ayuso G, Rabinovitch H, MacLean H, Marriott J, Racosta J, Arab L, Gimona M, Introna M, Blinkenberg M, Aghdami N, Ali R, Vosoughi R, Nicholas R, Marrie RA, Karimi S (2019) MEsenchymal StEm cells for multiple sclerosis (MESEMS): a randomized, double blind, cross-over phase I/II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis. Trials 20:263. https://doi.org/10.1186/s13063-019-3346-z

    Article  PubMed  PubMed Central  Google Scholar 

  • Unger RE, Dohle E, Kirkpatrick CJ (2015) Improving vascularization of engineered bone through the generation of pro-angiogenic effects in co-culture systems. Adv Drug Deliv Rev 94:116

    CAS  PubMed  Google Scholar 

  • Uth N, Mueller J, Smucker B, Yousefi AM (2017) Validation of scaffold design optimization in bone tissue engineering: finite element modeling versus designed experiments. Biofabrication. https://doi.org/10.1088/1758-5090/9/1/015023

  • Viswanathan S, Shi Y, Galipeau J, Krampera M, Leblanc K (2019) Mesenchymal stem versus stromal cells: International Society for Cell & Gene Therapy (ISCT Ò) mesenchymal stromal cell committee. Cytotherapy 21:1019–1024. https://doi.org/10.1016/j.jcyt.2019.08.002

    Article  CAS  PubMed  Google Scholar 

  • Volarevic V, Markovic BS, Harrell CR, Fellabaum C, Jovicic N, Djonov V, Arsenijevic N (2019) Use of mesenchymal stem cells in inflammatory bowel disease. Springer, Cham, pp 125–138

    Google Scholar 

  • Wang Z, Mithieux SM, Weiss AS (2019) Fabrication techniques for vascular and vascularized tissue engineering. Adv Healthc Mater 8:1900742. https://doi.org/10.1002/adhm.201900742

    Article  CAS  Google Scholar 

  • Warnke P, Springer I, Wiltfang PJ, Acil PY, Eufinger PH, Wehmöller M, Russo P, Bolte H, Sherry E, Behrens E, Terheyden PH (2004) Growth and transplantation of a custom vascularised bone graft in a man. Lancet. https://doi.org/10.1016/S0140-6736(04)16935-3

  • Wei Q, Frenette PS (2018) Niches for hematopoietic stem cells and their progeny. Immunity 48:632–648. https://doi.org/10.1016/J.IMMUNI.2018.03.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Winkler T, Sass FA, Duda GN, Schmidt-Bleek K (2018) A review of biomaterials in bone defect healing, remaining shortcomings and future opportunities for bone tissue engineering: the unsolved challenge. Bone J Res 7:232

    CAS  Google Scholar 

  • Worthley DL, Churchill M, Compton JT, Tailor Y, Rao M, Si Y, Levin D, Schwartz MG, Uygur A, Hayakawa Y, Gross S, Renz BW, Setlik W, Martinez AN, Chen X, Nizami S, Lee HG, Kang HP, Caldwell JM, Asfaha S, Westphalen CB, Graham T, Jin G, Nagar K, Wang H, Kheirbek MA, Kolhe A, Carpenter J, Glaire M, Nair A, Renders S, Manieri N, Muthupalani S, Fox JG, Reichert M, Giraud AS, Schwabe RF, Pradere JP, Walton K, Prakash A, Gumucio D, Rustgi AK, Stappenbeck TS, Friedman RA, Gershon MD, Sims P, Grikscheit T, Lee FY, Karsenty G, Mukherjee S, Wang TC (2015) Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell 160:269–284. https://doi.org/10.1016/j.cell.2014.11.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu H, Kang N, Wang Q, Dong P, Lv X, Cao Y, Xiao R (2015) The dose–effect relationship between the seeding quantity of human marrow mesenchymal stem cells and in vivo tissue-engineered bone yield. Cell Transplant. https://doi.org/10.3727/096368914X685393

  • Wuchter P, Vetter M, Saffrich R, Diehlmann A, Bieback K, Ho AD, Horn P (2016) Evaluation of GMP-compliant culture media for in vitro expansion of human bone marrow mesenchymal stromal cells. Exp Hematol 44:508–518. https://doi.org/10.1016/j.exphem.2016.02.004

    Article  CAS  PubMed  Google Scholar 

  • Zachar L, Bačenková D, Rosocha J (2016) Activation, homing, and role of the mesenchymal stem cells in the inflammatory environment. J Inflamm Res 9:231–240. https://doi.org/10.2147/JIR.S121994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zadpoor AA (2015) Bone tissue regeneration: the role of scaffold geometry. Biomater Sci 3:231

    CAS  PubMed  Google Scholar 

  • Zhao Q, Ren H, Han Z (2016) Mesenchymal stem cells: immunomodulatory capability and clinical potential in immune diseases. J Cell Immunother 2:3–20. https://doi.org/10.1016/j.jocit.2014.12.001

    Article  Google Scholar 

  • Zhao L, Chen S, Yang P, Cao H, Li L (2019) The role of mesenchymal stem cells in hematopoietic stem cell transplantation: prevention and treatment of graft-versus-host disease. Stem Cell Res Ther 10:182. https://doi.org/10.1186/s13287-019-1287-9

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhou BO, Yue R, Murphy MM, Peyer JG, Morrison SJ (2014) Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 15:154–168. https://doi.org/10.1016/j.stem.2014.06.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu H, Guo Z-K, Jiang X-X, Li H, Wang X-Y, Yao H-Y, Zhang Y, Mao N (2010) A protocol for isolation and culture of mesenchymal stem cells from mouse compact bone. Nat Protoc 5:550–560. https://doi.org/10.1038/nprot.2009.238

    Article  CAS  PubMed  Google Scholar 

  • Zuk PA, Zhu M, Mizuno H, Huang J, Futrell JW, Katz AJ, Benhaim P, Lorenz HP, Hedrick MH (2001) Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7:211–228

    CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the European Union Horizon 2020 Research and Innovation Programme under Marie Sklodowska-Curie grant agreement No. 657716 (to DMP), and by the Austrian Research Promotion Agency (FFG) grant No. 867803 (SINEM). This work was also supported by funding from the Slovenian Research Agency (J3-1749; to JZ). Research support to RO from the Biotechnology and Biological Sciences Research Council (BBSRC LO21071/1, BB/L00609X/1, BB/P017711/1), the UK Regenerative Medicine Platform Acellular/Smart Materials – 3D Architecture (MR/R015651/1), Rosetrees Trust, Wessex Medical Research, and the University of Southampton is gratefully acknowledged, along with the many useful discussions with past and current members of the Bone and Joint Research Group in Southampton, UK. The Figures were created using Mind the Graph. The authors thank Dr. Chris Berrie for scientific English editing of the manuscript.

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Authors and Affiliations

  1. Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia

    Janja Zupan

  2. Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, UK

    Daniel Tang & Richard O. C. Oreffo

  3. AUVA Trauma Research Center, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria

    Heinz Redl & Darja Marolt Presen

  4. Austrian Cluster for Tissue Regeneration, Vienna, Austria

    Heinz Redl & Darja Marolt Presen

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  1. Janja Zupan
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  2. Daniel Tang
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  3. Richard O. C. Oreffo
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  4. Heinz Redl
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  5. Darja Marolt Presen
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Correspondence to Darja Marolt Presen .

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Editors and Affiliations

  1. Tulane Univ. Sch. of Medicine, New Orleans, LA, USA

    Jeffrey M. Gimble

  2. AUVA Trauma Research Center, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria

    Darja Marolt Presen

  3. Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton, UK

    Richard O. C. Oreffo

  4. AUVA Trauma Research Center, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria

    Susanne Wolbank

  5. AUVA Trauma Research Center, Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Vienna, Austria

    Heinz Redl

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Zupan, J., Tang, D., Oreffo, R.O.C., Redl, H., Marolt Presen, D. (2020). Bone-Marrow-Derived Mesenchymal Stromal Cells: From Basic Biology to Applications in Bone Tissue Engineering and Bone Regeneration. In: Gimble, J., Marolt Presen, D., Oreffo, R., Wolbank, S., Redl, H. (eds) Cell Engineering and Regeneration. Reference Series in Biomedical Engineering(). Springer, Cham. https://doi.org/10.1007/978-3-319-08831-0_7

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