Abstract
Unlike the terminally differentiated somatic cells, stem cells are characterized by their unlimited, undifferentiated self-renewal, and differentiation potential to adopt diverse phenotypes, a property which is being exploited in cell-based therapy to repair injured organs or tissues. In the body, stem/progenitor cells are an essential part of the body’s intrinsic repair system in tissue injury to replace the damaged cells. Recent data indicate that the mechanism of stem cell therapy’s effectiveness may be due to cells’ paracrine activity more than to the replacement of the injured cells at the site of injury. The paracrine effect stems from their secretome that contains a significant number of growth factors, chemokines, cytokines, and exosomes. The cell secretome’s regulatory role has been validated in various physiological processes, including homing in of the cells to injured body sites, regulating apoptotic processes, proliferation, migration, and differentiation. The immunomodulatory and regenerative capacity of these paracrine factors plays an essential role in determining the therapeutic outcome after treatment with stem cells. As a cell-free regenerative therapeutic alternative, stem cell secretome has enormous potential to alleviate neurodegenerative disease, ischemic stroke, lung diseases, liver diseases, and renal diseases.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Abbreviations
- 6-OHDA:
-
6-hydroxydopamine
- AD:
-
Alzheimer’s disease
- AKI:
-
Acute kidney injury
- ALI:
-
Abnormalities underlying acute lung injury
- Ang-2:
-
Angiopoietin-2
- APAP:
-
Acetaminophen
- ASCs:
-
Adipose stem cells
- BM-MSCs:
-
Bone marrow-derived MSCs
- BNDF:
-
Brain-derived neurotrophic factor
- BPD:
-
Bronchopulmonary dysplasia
- CKD:
-
Chronic kidney disease
- CM:
-
Conditioned medium
- CNTF:
-
Ciliary neurotrophic factor
- COMT:
-
Catechol-O-methyltransferase
- EMT:
-
Epithelial to mesenchymal transition
- ESRD:
-
End-stage renal disease
- EVs:
-
Extracellular vesicles
- GDNF:
-
Glial cell line-derived neurotrophic factor
- hBM-MSCs:
-
Human BM-MSCs
- HGF:
-
Hepatocyte growth factor
- hMSCs:
-
Human MSCs
- hNPCs:
-
Human neural progenitor cells
- hUc-MSCs:
-
Human umbilical cord-derived MSCs
- IDO:
-
Indoleamine 2,3 dioxygenase
- IGF-1:
-
Insulin-like growth factor-1
- KGF:
-
Keratinocyte growth factor
- MAO-B:
-
Monoamine oxidase B
- MIP-2:
-
Macrophage inflammatory protein-2
- MMP-2:
-
Matrix metalloproteinase-2
- NCM:
-
Nonconditioned media
- NFkb:
-
Nuclear factor kappa-light-chain-enhancer of activated B cells
- PDGF-A:
-
Platelet-derived growth factor-AA
- PGE2:
-
Prostaglandin-E2 (PGE2 substantia nigra)
- STAT3:
-
Signal transducer and activator of transcription 3
- TGF-β:
-
Transforming growth factor-β
- TNF-α:
-
Tumor necrosis factor-alpha
- VCAM-1:
-
Vascular cell adhesion molecule 1
- VEGF:
-
Vascular endothelial growth factor
- VEGFR2:
-
VEGF receptor 2
- WJ-MSCs:
-
WJ-derived MSCs
References
Aggarwal S, Pittenger MF (2005) Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood 105(4):1815–1822. https://doi.org/10.1182/blood-2004-04-1559
Agrawal H, Shang H, Sattah AP et al (2014) Human adipose- derived stromal/stem cells demonstrate short-lived persistence after implantation in both an immunocompetent and an immunocompromised murine model. Stem Cell Res Ther 5(6):142. https://doi.org/10.1186/scrt532
Alfaifi M, Eom YW, Newsome PN et al (2018) Mesenchymal stromal cell therapy for liver diseases. J Hepatol 68(6):1272–1285. https://doi.org/10.1016/j.jhep.2018.01.030
Alfarano C, Roubeix C, Chaaya R et al (2012) Intraparenchymal injection of bone marrow mesenchymal stem cells reduces kidney fibrosis after ischemia-reperfusion in cyclosporine-immunosuppressed rats. Cell Transplant 21(9):2009–2019. https://doi.org/10.3727/096368912X640448
An SY, Jang YJ, Lim HJ et al (2017) Milk fat globule-EGF factor 8, secreted by mesenchymal stem cells, protects against liver fibrosis in mice. Gastroenterology 152(5):1174–1186. https://doi.org/10.1053/j.gastro.2016.12.003
Aslam M, Baveja R, Liang OD et al (2009) Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease. Am J Respir Crit Care Med 180(11):1122–1130. https://doi.org/10.1164/rccm.200902-0242OC
Bagheri-Mohammadi S, Karimian M, Alani B et al (2019) Stem cell-based therapy for Parkinson’s disease with a focus on human endometrium-derived mesenchymal stem cells. J Cell Physiol 234(2):1326–1335. https://doi.org/10.1002/jcp.27182
Banerjee S, Williamson DA, Habib N et al (2012) The potential benefit of stem cell therapy after stroke: an update. Vasc Health Risk Manag 8:569–580. https://doi.org/10.2147/VHRM.S25745
Bang OY, Lee JS, Lee PH et al (2005) Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 57(6):874–882. https://doi.org/10.1002/ana.20501
Baraniak PR, McDevitt TC (2010) Stem cell paracrine actions and tissue regeneration. Regen Med 5(1):121–143. https://doi.org/10.2217/rme.09.74
Beer L, Mildner M, Ankersmit HJ (2017) Cell secretome based drug substances in regenerative medicine: when regulatory affairs meet basic science. Ann Transl Med 5(7):170. https://doi.org/10.21037/atm.2017.03.50
Benskey MJ, Perez RG, Manfredsson FP (2016) The contribution of alpha synuclein to neuronal survival and function-implications for Parkinson’s disease. J Neurochem 137(3):331–359. https://doi.org/10.1111/jnc.13570
Bermudez MA, Sendon-Lago J, Eiro N et al (2015) Corneal epithelial wound healing and bactericidal effect of conditioned medium from human uterine cervical stem cells. Invest Ophthalmol Vis Sci 56(2):983–992. https://doi.org/10.1167/iovs.14-15859
Bermudez MA, Sendon-Lago J, Seoane S et al (2016) Anti-inflammatory effect of conditioned medium from human uterine cervical stem cells in uveitis. Exp Eye Res 149:84–92. https://doi.org/10.1016/j.exer.2016.06.022
Bhang SH, Lee S, Shin JY et al (2014) Efficacious and clinically relevant conditioned medium of human adipose-derived stem cells for therapeutic angiogenesis. Mol Ther 22(4):862–872. https://doi.org/10.1038/mt.2013.301
Bhasin A, Srivastava MVP, Kumaran SS et al (2011) Autologous mesenchymal stem cells in chronic stroke. Cerebrovasc Dis Extra 1(1):93–104. https://doi.org/10.1159/000333381
Bi BY, Schmitt R, Israilova M et al (2007) Stromal cells protect against acute tubular injury via an endocrine effect. J Am Soc Nephrol 18(9):2486–2496. https://doi.org/10.1681/ASN.2007020140
Biju KC, Santacruz RA, Chen C et al (2013) Bone marrow-derived microglia-based neurturin delivery protects against dopaminergic neurodegeneration in a mouse model of Parkinson’s disease. Neurosci Lett 535:24–29. https://doi.org/10.1016/j.neulet.2012.12.034
van Bruggen N, Thibodeaux H, Palmer JT et al (1999) VEGF antagonism reduces edema formation and tissue damage after ischemia/reperfusion injury in the mouse brain. J Clin Invest 104(11):1613–1620. https://doi.org/10.1172/JCI8218
Caplan AI, Dennis JE (2006) Mesenchymal stem cells as trophic mediators. J Cell Biochem 98(5):1076–1084. https://doi.org/10.1002/jcb.20886
Chang CP, Chio CC, Cheong CU et al (2013) Hypoxic preconditioning enhances the therapeutic potential of the secretome from cultured human mesenchymal stem cells in experimental traumatic brain injury. Clin Sci 124(3):165–176. https://doi.org/10.1042/CS20120226
Chen J, Li Y, Wang L et al (2001a) Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci 189(1–2):49–57. https://doi.org/10.1016/s0022-510x(01)00557-3
Chen J, Li Y, Wang L et al (2001b) Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 32(4):1005–1011. https://doi.org/10.1161/01.str.32.4.1005
Chen J, Sanberg PR, Li Y et al (2001c) Intravenous administration of human umbilical cord blood reduces behavioral deficits after stroke in rats. Stroke 32(11):2682–2688. https://doi.org/10.1161/hs1101.098367
Chen J, Zhang ZG, Li Y et al (2003) Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res 92(6):692–699. https://doi.org/10.1161/01.RES.0000063425.51108.8D
Chen J, Ning R, Zacharek A et al (2016) MiR-126 contributes to human umbilical cord blood cell-induced neurorestorative effects after stroke in type-2 diabetic mice. Stem Cells 34(1):102–113. https://doi.org/10.1002/stem.2193
Collins AJ, Foley RN, Gilbertson DT et al (2015) United States Renal Data System public health surveillance of chronic kidney disease and end-stage renal disease. Kidney Int Suppl 5(1):2–7. https://doi.org/10.1038/kisup.2015.2
Cova L, Armentero M-T, Zennaro E et al (2010) Multiple neurogenic and neurorescue effects of human mesenchymal stem cell after transplantation in an experimental model of Parkinson’s disease. Brain Res 1311:12–27. https://doi.org/10.1016/j.brainres.2009.11.041
Cova L, Bossolasco P, Armentero M-T et al (2012) Neuroprotective effects of human mesenchymal stem cells on neural cultures exposed to 6-hydroxydopamine: implications for reparative therapy in Parkinson’s disease. Apoptosis 17(3):289–304. https://doi.org/10.1007/s10495-011-0679-9
Crivelli B, Chlapanidas T, Perteghella S et al (2017) Mesenchymal stem/stromal cell extracellular vesicles: from active principle to next generation drug delivery system. J Control Release 262:104–117. https://doi.org/10.1016/j.jconrel.2017.07.023
Da Silva AF, Silva K, Reis LA et al (2015) Bone marrow-derived mesenchymal stem cells and their conditioned medium attenuate fibrosis in an irreversible model of unilateral ureteral obstruction. Cell Transplant 24(12):2657–2666. https://doi.org/10.3727/096368915X687534
Damania A, Jaiman D, Teotia AK et al (2018) Mesenchymal stromal cell-derived exosome- rich fractionated secretome confers a hepatoprotective effect in liver injury. Stem Cell Res Ther 9(1):31. https://doi.org/10.1186/s13287-017-0752-6
Deans RJ, Moseley AB (2000) Mesenchymal stem cells: biology and potential clinical uses. Exp Hematol 28(8):875–884. https://doi.org/10.1016/s0301-472x(00)00482-3
Deng YB, Ye WB, Hu ZZ et al (2010) Intravenously administered BMSCs reduce neuronal apoptosis and promote neuronal proliferation through the release of VEGF after stroke in rats. Neurol Res 32(2):148–156. https://doi.org/10.1179/174313209X414434
Deng M, Xiao H, Zhang H et al (2017) Mesenchymal stem cell-derived extracellular vesicles ameliorates hippocampal synaptic impairment after transient global ischemia. Front Cell Neurosci 11:205. https://doi.org/10.3389/fncel.2017.00205
Ding DC, Shyu WC, Chiang MF et al (2007) Enhancement of neuroplasticity through upregulation of beta1-integrin in human umbilical cord-derived stromal cell implanted stroke model. Neurobiol Dis 27(3):339–353. https://doi.org/10.1016/j.nbd.2007.06.010
Docheva D, Popov C, Mutschler W et al (2007) Human mesenchymal stem cells in contact with their environment: surface characteristics and the integrin system. J Cell Mol Med 11(1):21–38. https://doi.org/10.1111/j.1582-4934.2007.00001.x
Doeppner TR, Herz J, Görgens A et al (2015) Extracellular vesicles improve post-stroke neuroregeneration and prevent postischemic immunosuppression. Stem Cells Transl Med 4(10):1131–1143. https://doi.org/10.5966/sctm.2015-0078
Drago D, Cossetti C, Iraci N et al (2013) The stem cell secretome and its role in brain repair. Biochimie 95(12):2271–2285. https://doi.org/10.1016/j.biochi.2013.06.020
Eiro N, Sendon-Lago J, Seoane S et al (2014) Potential therapeutic effect of the secretome from human uterine cervical stem cells against both cancer and stromal cells compared with adipose tissue stem cells. Oncotarget 5(21):10692–10708. https://doi.org/10.18632/oncotarget.2530
Elmadbouh I, Haider HK, Jean-Baptiste Michel JB, Ashraf M (2008) Non-viral vector gene modification of stem cells for myocardial repair. Mol Med 14(1-2):79–86
Elmadbouh I, Haider HK, Ashraf M, Chachques J-C (2011) Preconditioning of human skeletal myoblast with stromal cell-derived factor-1α promotes cytoprotective effects against oxidative and anoxic stress. Int J Stem Cells 4:50–60
English K, French A, Wood KJ (2010) Mesenchymal stromal cells: facilitators of successful transplantation? Cell Stem Cell 7(4):431–442. https://doi.org/10.1016/j.stem.2010.09.009
Fang X, Neyrinck AP, Matthay MA et al (2010) Allogeneic human mesenchymal stem cells restore epithelial protein permeability in cultured human alveolar type II cells by secretion of angiopoietin-1. J Biol Chem 285(34):26211–26222. https://doi.org/10.1074/jbc.M110.119917
Feigin VL, Forouzanfar MH, Krishnamurthi R et al (2014) Global and regional burden of stroke during 1990–2010: findings from the Global Burden of Disease Study 2010. Lancet 383(9913):245–255. https://doi.org/10.1016/s0140-6736(13)61953-4
Feng L, Meng H, Wu F et al (2008) Olfactory ensheathing cells conditioned medium prevented apoptosis induced by 6-OHDA in PC12 cells through modulation of intrinsic apoptotic pathways. Int J Dev Neurosci 26(3–4):323–329. https://doi.org/10.1016/j.ijdevneu.2008.01.003
Feng ST, Wang ZZ, Yuan YH et al (2020) Dynamin-related protein 1: a protein critical for mitochondrial fission, mitophagy, and neuronal death in Parkinson’s disease. Pharmacol Res 151(104553). https://doi.org/10.1016/j.phrs.2019.104553
Fung ME, Thebaud B (2014) Stem cell-based therapy for neonatal lung disease: it is in the juice. Pediatr Res 75(1–1):2–7. https://doi.org/10.1038/pr.2013.176
Gao J, Dennis JE, Muzic RF et al (2001) The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 169(1):12–20. https://doi.org/10.1159/000047856
Gazdic M, Markovic BS, Arsenijevic A et al (2018) Crosstalk between mesenchymal stem cells and T regulatory cells is crucially important for the attenuation of acute liver injury. Liver Transpl 24(5):687–702. https://doi.org/10.1002/lt.25049
Ghazavi H, Hoseini SJ, Ebrahimzadeh-Bideskan A et al (2017) Fibroblast growth factor type 1 (FGF1)-overexpressed adipose-derived mesenchymal stem cells (AD-MSCFGF1) induce neuroprotection and functional recovery in a rat stroke model. Stem Cell Rev Rep 13(5):670–685. https://doi.org/10.1007/s12015-017-9755-z
Graf T (2002) Differentiation plasticity of hematopoietic cells. Blood 99(9):3089–3101. https://doi.org/10.1182/blood.v99.9.3089
Greenberg DA, Jin K (2013) Vascular endothelial growth factors (VEGFs) and stroke. Cell Mol Life Sci 70(10):1753–1761. https://doi.org/10.1007/s00018-013-1282-8
Guérin C (2017) Prone positioning acute respiratory distress syndrome patients. Ann Transl Med 5(14):289. https://doi.org/10.21037/atm.2017.06.63
Guery BP, Mason CM, Dobard EP et al (1997) Keratinocyte growth factor increases transalveolar sodium reabsorption in normal and injured rat lungs. Am J Respir Crit Care Med 155(5):1777–1784. https://doi.org/10.1164/ajrccm.155.5.9154891
van Haaften T, Byrne R, Bonnet S et al (2009) Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am J Respir Crit Care Med 180(11):1131–1142. https://doi.org/10.1164/rccm.200902-0179OC
Haga S, Terui K, Zhang HQ et al (2003) Stat3 protects against Fas-induced liver injury by redox-dependent and -independent mechanisms. J Clin Invest 112(7):989–998. https://doi.org/10.1172/JCI17970
Haga H, Yan IK, Borrelli DA et al (2017a) Extracellular vesicles from bone marrow-derived mesenchymal stem cells protect against murine hepatic ischemia/reperfusion injury. Liver Transpl 23(6):791–803. https://doi.org/10.1002/lt.24770
Haga H, Yan IK, Tkahashi K et al (2017b) Extracellular vesicles from bone marrow-derived mesenchymal stem cells improve survival from lethal hepatic failure in mice. Stem Cells Transl Med 6(4):1262–1272. https://doi.org/10.1002/sctm.16-0226
Haider HK (2018) The aging stem cells and cardiac reparability: lesson learnt from clinical studies is that old is not always gold. Regen Med 13(4):457–475
Haider KH, Aramini B (2020) “Mircrining” the injured heart with stem cell-derived exosomes: an emerging strategy of cell-free therapy. Stem Cell Res Ther 11(1):23
Haider HK, Ashraf M (2010) Preconditioning and stem cell survival. J Cardiovasc Trans Res 3:89–102
Haider HK, Ashraf M (2012) Preconditioning approach in stem cell therapy for the treatment of infarcted heart. Prog Mol Biol Transl Sci 111:323–356. https://doi.org/10.1016/B978-0-12-398459-3.00015-0.
Haider HK, Jiang S, Niagara MI, Ashraf M (2008) IGF-I over expressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of SDF-1α/CXCR4 signaling to promote myocardial repair. Circulat Res 103:1300–1308
Hansmann G, Fernandez-Gonzalez A, Aslam M et al (2012) Mesenchymal stem cell-mediated reversal of bronchopulmonary dysplasia and associated pulmonary hypertension. Pulm Circ 2(2):170–181. https://doi.org/10.4103/2045-8932.97603
Hassan Famian M, Montazer Saheb S, Montaseri A (2017) Conditioned medium of Wharton’s jelly derived stem cells can enhance the cartilage specific genes expression by chondrocytes in monolayer and mass culture systems. Adv Pharm Bull 7(1):123–130. https://doi.org/10.15171/apb.2017.016
Hoban DB, Howard L, Dowd E (2015) GDNF-secreting mesenchymal stem cells provide localized neuroprotection in an inflammation-driven rat model of Parkinson’s disease. Neuroscience 303:402–411. https://doi.org/10.1016/j.neuroscience.2015.07.014
Hofstetter CP, Schwarz EJ, Hess D et al (2002) Marrow stromal cells form guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci U S A 99(4):2199–2204. https://doi.org/10.1073/pnas.042678299
Honmou O, Houkin K, Matsunaga T et al (2011) Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke. Brain 134(Pt6):1790–1807. https://doi.org/10.1093/brain/awr063
Horita Y, Honmou O, Harada K 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(7):1495–1504. https://doi.org/10.1002/jnr.21056
Hu SL, He HL, Pan C et al (2014) The effect of prone positioning on mortality in patients with acute respiratory distress syndrome: a meta-analysis of randomized controlled trials. Crit Care 18(3):R109. https://doi.org/10.1186/cc13896
Huang B, Cheng XX, Wang HF et al (2016) Mesenchymal stem cells and their secreted molecules predominantly ameliorate fulminant hepatic failure and chronic liver fibrosis in mice respectively. J Transl Med 14:45. https://doi.org/10.1186/s12967-016-0792-1
Huh JW, Kim SY, Lee JH et al (2011) Bone marrow cells repair cigarette smoke-induced emphysema in rats. Am J Physiol Lung Cell Mol Physiol 301(3):L255–L266
Hyman C, Hofer M (1991) BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. Nature 350(6315):230–232. https://doi.org/10.1152/ajplung.00253.2010
Igura K, Haider HK, RPH A, Sheriff S, Ashraf M (2011) Neuropeptide-Y (NPY) and NPY Y5 receptor (Y5R) interaction restores impaired growth potential of ageing bone marrow stromal cells. Rejuven Res 14(4):393–403
Imberti B, Morigi M, Tomasoni S et al (2007) Insulin-like growth factor-1 sustains stem cell mediated renal repair. J Am Soc Nephrol 18(11):2921–2928. https://doi.org/10.1681/ASN.2006121318
Ionescu L, Byrne RN, van Haaften T et al (2012a) Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action. Am J Physiol Lung Cell Mol Physiol 303(11):L967–L977. https://doi.org/10.1152/ajplung.00144.2011
Ionescu LI, Alphonse RS, Arizmendi N et al (2012b) Airway delivery of soluble factors from plastic-adherent bone marrow cells prevents murine asthma. Am J Respir Cell Mol Biol 46(2):207–216. https://doi.org/10.1165/rcmb.2010-0391OC
Ishizaka S, Horie N, Satoh K et al (2013) Intra-arterial cell transplantation provides timing-dependent cell distribution and functional recovery after stroke. Stroke 44(3):720–726. https://doi.org/10.1161/STROKEAHA.112.677328
Jang YJ, An SY, Kim JH (2017) Identification of MFGE8 in mesenchymal stem cell secretome as an anti-fibrotic factor in liver fibrosis. BMB Rep 50(2):58–59. https://doi.org/10.5483/bmbrep.2017.50.2.012
Jarmalavičiūtė A, Tunaitis V, Pivoraitė U et al (2015) Exosomes from dental pulp stem cells rescue human dopaminergic neurons from 6-hydroxy-dopamine–induced apoptosis. Cytotherapy 17(7):932–939. https://doi.org/10.1016/j.jcyt.2014.07.013
Jeong CH, Kim SM, Lim JY et al (2014) Mesenchymal stem cells expressing brain-derived neurotrophic factor enhance endogenous neurogenesis in an ischemic stroke model. Biomed Res Int 2014:1–10. https://doi.org/10.1155/2014/129145
Jiang W, Ma A, Wang T et al (2006) Intravenous transplantation of mesenchymal stem cells improves cardiac performance after acute myocardial ischemia in female rats. Transpl Int 19(7):570–580. https://doi.org/10.1111/j.1432-2277.2006.00307.x
Jiang S, Haider HK, Niagara MI, Lu G, Ashraf M (2008) Stable therapeutic effects of mesenchymal stem cell based multiple gene delivery for cardiac repair. Cardiovasc Res 77(3):525–533
Jiang Y, Zhu W, Zhu J et al (2013) Feasibility of delivering mesenchymal stem cells via catheter to the proximal end of the lesion artery in patients with stroke in the territory of the middle cerebral artery. Cell Transplant 22(12):2291–2298. https://doi.org/10.3727/096368912X658818
Johnston PA, Grandis JR (2011) STAT3 signaling: anticancer strategies and challenges. Mol Interv 11(1):18–26. https://doi.org/10.1124/mi.11.1.4
Jun D, Garat C, West J et al (2011) The pathology of bleomycin-induced fibrosis is associated with loss of resident lung mesenchymal stem cells that regulate effector T-cell proliferation. Stem Cells 29(4):725–735. https://doi.org/10.1002/stem.604
Justewicz DM, Shokes JE, Reavis B et al (2012) Characterization of the human smooth muscle cell secretome for regenerative medicine. Tissue Eng Part C Methods 18(10):797–816. https://doi.org/10.1089/ten.TEC.2012.0054
Katagiri W, Watanabe J, Toyama N et al (2017) Clinical study of bone regeneration by conditioned medium from mesenchymal stem cells after maxillary sinus floor elevation. Implant Dent 26(4):607–612. https://doi.org/10.1097/ID.0000000000000618
Kavianpour M, Saleh M, Verdi J (2020) The role of mesenchymal stromal cells in immune modulation of COVID-19: focus on cytokine storm. Stem Cell Res Ther 11:404. https://doi.org/10.1186/s13287-020-01849-7
Kim HW, Ashraf M, Jiang S, Haider HK (2012a) Stem cell based delivery of hypoxamir-210 to the infarcted heart: implications on stem cell survival and preservation of the infarcted heart function. J Mol Med 90(9):997–1010
Kim HW, Malik F, Durrani S, Ashraf M, Jiang S, Haider HK (2012b) Concomitant activation of mir-107/pdcd10 and hypoxamir-210/casp8ap2 and their role in cytoprotection during ischemic preconditioning of stem cells. Antioxidant Redox Signal 17(8):1053–1065
Kim SY, Lee JH, Kim HJ et al (2012c) Mesenchymal stem cell-conditioned media recovers lung fibroblasts from cigarette smoke-induced damage. Am J Physiol Lung Cell Mol Physiol 302(9):L891–L908. https://doi.org/10.1152/ajplung.00288.2011
Kim DK, Nishida H, An SY et al (2016a) Chromatographically isolated CD63+ CD81+ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI. Proc Natl Acad Sci U S A 113(1):170–175. https://doi.org/10.1073/pnas.1522297113
Kim MJ, Kim ZH, Kim SM et al (2016b) Conditioned medium derived from umbilical cord mesenchymal stem cells regenerates atrophied muscles. Tissue Cell 48(5):533–543. https://doi.org/10.1016/j.tice.2016.06.010
Koh SH, Kim KS, Choi MR et al (2008) Implantation of human umbilical cord-derived mesenchymal stem cells as a neuroprotective therapy for ischemic stroke in rats. Brain Res 1229:233–248. https://doi.org/10.1016/j.brainres.2008.06.087
van Koppen A, Joles JA, van Balkom BWM et al (2012) Human embryonic mesenchymal stem cell-derived conditioned medium rescues kidney function in rats with established chronic kidney disease. PLoS One 7(6):e38746. https://doi.org/10.1371/journal.pone.0038746
Kordelas L, Rebmann V, Ludwig AK et al (2014) MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 28(4). https://doi.org/10.1038/leu.2014.41
Kurozumi K, Nakamura K, Tamiya T et al (2004) BDNF Gene-modified mesenchymal stem cells promote functional recovery and reduce infarct size in the rat middle cerebral artery occlusion model. Mol Ther 9(2):189–197. https://doi.org/10.1016/j.ymthe.2003.10.012
Kurozumi K, Nakamura K, Tamiya T et al (2005) Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model. Mol Ther 11(1):96–104. https://doi.org/10.1016/j.ymthe.2004.09.020
Lai VK, Ashraf M, Jiang S, Haider HK (2012) MicroRNA-143 is critical regulator of cell cycle activity in stem cells with co-overexpression of Akt and angiopoietin-1 via transcriptional regulation of Erk5/Cyclin D1 signaling. Cell Cycle 11(4):667–677
Lange C, Tögel F, Ittrich H et al (2005) Administered mesenchymal stem cells enhance recovery from ischemia/reperfusion-induced acute renal failure in rats. Kidney Int 68(4):1613–1617. https://doi.org/10.1111/j.1523-1755.2005.00573.x
Lee JW, Fang X, Gupta N et al (2009) Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc Natl Acad Sci U S A 106(38):16357–16362. https://doi.org/10.1073/pnas.0907996106
Lee JS, Hong JM, Moon GJ et al (2010) A long-term follow-up study of intravenous autologous mesenchymal stem cell transplantation in patients with ischemic stroke. Stem Cells 28(6):1099–1106. https://doi.org/10.1002/stem.430
Lee JW, Fang X, Krasnodembskaya A et al (2011) Concise review: mesenchymal stem cells for acute lung injury: role of paracrine soluble factors. Stem Cells 29(6):913–919. https://doi.org/10.1002/stem.643
Lee JW, Krasnodembskaya A, McKenna DH et al (2013) Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria. Am J Respir Crit Care Med 187(7):751–760. https://doi.org/10.1164/rccm.201206-0990OC
Lee KC, Lin HC, Huang YH et al (2015a) Allo-transplantation of mesenchymal stem cells attenuates hepatic injury through IL1Ra dependent macrophage switch in a mouse model of liver disease. J Hepatol 63(6):1405–1412. https://doi.org/10.1016/j.jhep.2015.07.035
Lee SC, Jeong HJ, Lee SK et al (2015b) Lipopolysaccharide preconditioning of adipose-derived stem cells improves liver-regenerating activity of the secretome. Stem Cell Res Ther 6:75. https://doi.org/10.1186/s13287-015-0072-7
Lee JY, Kim E, Choi SM et al (2016) Microvesicles from brain-extract-treated mesenchymal stem cells improve neurological functions in a rat model of ischemic stroke. Sci Rep 6:33038. https://doi.org/10.1038/srep33038
Legaki E, Roubelakis MG, Theodoropoulos GE et al (2016) Therapeutic potential of secreted molecules derived from human amniotic fluid mesenchymal stem/stroma cells in a mice model of colitis. Stem Cell Rev 12(5):604–612. https://doi.org/10.1007/s12015-016-9677-1
Li Y, Chen J, Chen XG et al (2002) Human marrow stromal cell therapy for stroke in rat: neurotrophins and functional recovery. Neurology 59(4):514–523. https://doi.org/10.1212/wnl.59.4.514
Li TF, Yan YM, Wang BY et al (2013) Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis. Stem Cells Dev 22(6):845–854. https://doi.org/10.1089/scd.2012.0395
Lin YC, Ko TL, Shih YH et al (2011) Human umbilical mesenchymal stem cells promote recovery after ischemic stroke. Stroke 42(7):2045–2053. https://doi.org/10.1161/STROKEAHA.110.603621
Liu H, Honmou O, Harada K et al (2006) Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia. Brain 129(Pt 10):2734–2745. https://doi.org/10.1093/brain/awl207
Liu XS, Li JF, Wang SS et al (2014) Human umbilical cord mesenchymal stem cells infected with adenovirus expressing HGF promote regeneration of damaged neuron cells in a Parkinson’s disease model. Biomed Res Int 2014(909657). https://doi.org/10.1155/2014/909657
Liu Q, Qin Q, Sun H et al (2018) Neuroprotective effect of olfactory ensheathing cells co-transfected with Nurr1 and Ngn2 in both in vitro and in vivo models of Parkinson’s disease. Life Sci 194:168–176. https://doi.org/10.1016/j.lfs.2017.12.038
Maggini J, Mirkin G, Bognanni I et al (2010) Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile. PLoS One 5(2):e9252. https://doi.org/10.1371/journal.pone.0009252
Maguire G (2013) Stem cell therapy without the cells. Commun Integr Biol 6(6):e26631. https://doi.org/10.4161/cib.26631
Makhlough A, Shekarchian S, Moghadasali R et al (2018) Bone marrow-mesenchymal stromal cell infusion in patients with chronic kidney disease: a safety study with 18 months of follow-up. Cytotherapy 20(5):660–669. https://doi.org/10.1016/j.jcyt.2018.02.368
Manne S, Kondru N, Jin H et al (2020) Alpha-Synuclein real-time quaking-induced conversion in the submandibular glands of Parkinson’s disease patients. Mov Disord 35(2):268–278. https://doi.org/10.1002/mds.27907
Marote A, Teixeira FG, Mendes-Pinheiro B et al (2016) MSCs-derived exosomes: cell-secreted nanovesicles with regenerative potential. Front Pharmacol 7:231. https://doi.org/10.3389/fphar.2016.00231
McMeekin P, White P, James MA et al (2017) Estimating the number of UK stroke patients eligible for endovascular thrombectomy. Eur Stroke J 2(4):319–326. https://doi.org/10.1177/2396987317733343
Mendes-Pinheiro B, Teixeira FG, Anjo SI et al (2018) Secretome of undifferentiated neural progenitor cells induces histological and motor improvements in a rat model of Parkinson’s disease. Stem Cells Transl Med 7(11):829–838. https://doi.org/10.1002/sctm.18-0009
Meyerrose T, Olson S, Pontow S et al (2010) Mesenchymal stem cells for the sustained in vivo delivery of bioactive factors. Adv Drug Deliv Rev 62(12):1167–1174. https://doi.org/10.1016/j.addr.2010.09.013
Miki Y, Nonoguchi N, Ikeda N et al (2007) Vascular endothelial growth factor gene-transferred bone marrow stromal cells engineered with a herpes simplex virus type 1 vector can improve neurological deficits and reduce infarction volume in rat brain ischemia. Neurosurgery 61(3):586–595. https://doi.org/10.1227/01.NEU.0000290907.30814.42
Mita T, Furukawa-Hibi Y, Takeuchi H et al (2015) Conditioned medium from the stem cells of human dental pulp improves cognitive function in a mouse model of Alzheimer’s disease. Behav Brain Res 293:189–197. https://doi.org/10.1016/j.bbr.2015.07.043
Moloney TC, Rooney GE, Barry FP et al (2010) Potential of rat bone marrow-derived mesenchymal stem cells as vehicles for delivery of neurotrophins to the Parkinsonian rat brain. Brain Res 1359:33–43. https://doi.org/10.1016/j.brainres.2010.08.040
Morigi M, Introna M, Imberti B et al (2008) Human bone marrow mesenchymal stem cells accelerate recovery of acute renal injury and prolong survival in mice. Stem Cells 26(8):2075–2082. https://doi.org/10.1634/stemcells.2007-0795
Niagara MI, Jiang S, Ashraf M, Haider HK (2012) Activation of IL11/STAT-3 pathway by preconditioning blocks apoptotic cascade in human skeletal myoblasts under oxidant stress. Regen Med 7(1):47–57
Nomura T, Honmou O, Harada K et al (2005) I.V. infusion of brain-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in adult rat. Neuroscience 136(1):161–169. https://doi.org/10.1016/j.neuroscience.2005.06.062
Oh SH, Choi C, Chang DJ et al (2015) Early neuroprotective effect with lack of long-term cell replacement effect on experimental stroke after intra-arterial transplantation of adipose-derived mesenchymal stromal cells. Cytotherapy 17(8):1090–1103. https://doi.org/10.1016/j.jcyt.2015.04.007
Oh SH, Kim HN, Park HJ et al (2017) The cleavage effect of mesenchymal stem cell and its derived matrix metalloproteinase-2 on extracellular α-synuclein aggregates in Parkinsonian models. Stem Cells Transl Med 6(3):949–961. https://doi.org/10.5966/sctm.2016-0111
Onda T, Honmou O, Harada K et al (2008) Therapeutic benefits by human mesenchymal stem cells (hMSCs) and Ang-1 gene-modified hMSCs after cerebral ischemia. J Cereb Blood Flow Metab 28(2):329–340. https://doi.org/10.1038/sj.jcbfm.9600527
Osugi M, Katagiri W, Yoshimi R (2012) Conditioned media from mesenchymal stem cells enhanced bone regeneration in rat calvarial bone defects. Tissue Eng Part A 18(13–14):1479–1489. https://doi.org/10.1089/ten.TEA.2011.0325
Otero-Ortega L, Laso -García F, Gómez -de Frutos MDC et al (2017) White matter repair after extracellular vesicles administration in an experimental animal model of subcortical stroke. Sci Rep 7:44433. https://doi.org/10.1038/srep44433
Papazian L, Forel JM, Gacouin A et al (2010) Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 363(12):1107–1116. https://doi.org/10.1056/NEJMoa1005372
Parekkadan B, van Poll D, Megeed Z et al (2007) Immunomodulation of activated hepatic stellate cells by mesenchymal stem cells. Biochem Biophys Res Commun 363(2):247–252. https://doi.org/10.1016/j.bbrc.2007.05.150
Parga JA, García-Garrote M, Martínez S et al (2018) Prostaglandin EP2 receptors mediate mesenchymal stromal cell-neuroprotective effects on dopaminergic neurons. Mol Neurobiol 55(6):4763–4776. https://doi.org/10.1007/s12035-017-0681-5
Park BS, Kim WS, Choi JS et al (2010) Hair growth stimulated by conditioned medium of adipose-derived stem cells is enhanced by hypoxia: evidence of increased growth factor secretion. Biomed Res 31(1):27–34. https://doi.org/10.2220/biomedres.31.27
Phinney DG, Prockop DJ (2007) Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair—current views. Stem Cells 25(11):2896–2902. https://doi.org/10.1634/stemcells.2007-0637
Pierro M, Ionescu L, Montemurro T et al (2013) Short-term, long-term and paracrine effect of human umbilical cord- derived stem cells in lung injury prevention and repair in experimental bronchopulmonary dysplasia. Thorax 68(5):475–484. https://doi.org/10.1136/thoraxjnl-2012-202323
Polazzi E, Altamira LEP, Eleuteri S et al (2009) Neuroprotection of microglial conditioned medium on 6-hydroxydopamine-induced neuronal death: role of transforming growth factor beta-2. J Neurochem 110(2):545–556. https://doi.org/10.1111/j.1471-4159.2009.06117.x
Polymeropoulos MH, Lavedan C, Leroy E et al (1997) Mutation in the alpha-synuclein gene identified in families with Parkinson’s disease. Science 276(5321):2045–2047. https://doi.org/10.1126/science.276.5321.2045
Rajan TS, Giacoppo S, Diomede F et al (2016) The secretome of periodontal ligament stem cells from MS patients protects against EAE. Sci Rep 6:38743. https://doi.org/10.1038/srep38743
Ramos TL, Sánchez-Abarca LI, Muntión S et al (2016) MSC surface markers (CD44, CD73, and CD90) can identify human MSC-derived extracellular vesicles by conventional flow cytometry. Cell Commun Signal 14:2. https://doi.org/10.1186/s12964-015-0124-8
Ren GW, Zhang LY, Zhao X et al (2008) Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2(2):141–150. https://doi.org/10.1016/j.stem.2007.11.014
Rovini A, Gurnev PA, Beilina A et al (2019) Molecular mechanism of olesoxime-mediated neuroprotection through targeting alpha-synuclein interaction with mitochondrial VDAC. Cell Mol Life Sci 77(18):3611–3626. https://doi.org/10.1007/s00018-019-03386-w
Rubenfeld GD, Caldwell E, Peabody E et al (2005) Incidence and outcomes of acute lung injury. N Engl J Med 353(16):1685–1693. https://doi.org/10.1056/NEJMoa050333
Ruster B, Gottig S, Ludwig RJ et al (2006) Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells. Blood 108(12):3938–3944. https://doi.org/10.1182/blood-2006-05-025098
Sadan O, Bahat-Stromza M, Barhum Y et al (2009) Protective effects of neurotrophic factor–secreting cells in a 6-OHDA rat model of Parkinson disease. Stem Cells Dev 18(8):1179–1190. https://doi.org/10.1089/scd.2008.0411
Safi R, Gardaneh M, Panahi Y et al (2012) Optimized quantities of GDNF overexpressed by engineered astrocytes are critical for protection of neuroblastoma cells against 6-OHDA toxicity. J Mol Neurosci 46(3):654–665. https://doi.org/10.1007/s12031-011-9654-8
Salgado AJ, Sousa JC, Costa BM et al (2015) Mesenchymal stem cells secretome as a modulator of the neurogenic niche: basic insights and therapeutic opportunities. Front Cell Neurosci 9:249. https://doi.org/10.3389/fncel.2015.00249
Saran R, Robinson B, Abbott KC et al (2017) US renal data system 2016 annual data report: epidemiology of kidney disease in the United States. Am J Kidney Dis 69(3 Suppl 1):A7–A8. https://doi.org/10.1053/j.ajkd.2016.12.004
Schäbitz WR, Sommer C, Zoder W et al (2000) Intravenous brain-derived neurotrophic factor reduces infarct size and counterregulates Bax and Bcl-2 expression after temporary focal cerebral ischemia. Stroke 31(9):2212–2217. https://doi.org/10.1161/01.str.31.9.2212
Schäbitz WR, Steigleder T, Cooper-Kuhn CM et al (2007) Intravenous brain-derived neurotrophic factor enhances poststroke sensorimotor recovery and stimulates neurogenesis. Stroke 38(7):2165–2172. https://doi.org/10.1161/STROKEAHA.106.477331
Semedo P, Correa-Costa M, Cenedeze MA et al (2009) Mesenchymal stem cells attenuate renal fibrosis through immune modulation and remodeling properties in a rat remnant kidney model. Stem Cells 27(12):3063–3073. https://doi.org/10.1002/stem.214
Sevivas N, Teixeira FG, Portugal R et al (2016) Mesenchymal stem cell secretome: a potential tool for the prevention of muscle degenerative changes associated with chronic rotator cuff tears. Am J Sports Med 45(1):179–188. https://doi.org/10.1177/0363546516657827
Shahid MS, Lasheen W, Haider HK (2016) Modest outcome of clinical trials with bone marrow cells for myocardial repair: is the autologous source of cells the prime culprit? J Thorac Dis 8(10):E1371–E1374
Shichinohe H, Ishihara T, Takahashi K et al (2015) Bone marrow stromal cells rescue ischemic brain by trophic effects and phenotypic change toward neural cells. Neurorehabil Neural Repair 29(1):80–89. https://doi.org/10.1177/1545968314525856
Shintani A, Nakao N, Kakishita K et al (2007) Protection of dopamine neurons by bone marrow stromal cells. Brain Res 1186:48–55. https://doi.org/10.1016/j.brainres.2007.09.086
Silversides JA, Ferguson ND (2013) Clinical review: acute respiratory distress syndrome-clinical ventilator management and adjunct therapy. Crit Care 17(2):225. https://doi.org/10.1186/cc11867
Steinberg GK, Kondziolka D, Wechsler LR et al (2016) Clinical outcomes of transplanted modified bone marrow-derived mesenchymal stem cells in stroke: a phase 1/2a study. Stroke 47(7):1817–1824. https://doi.org/10.1161/STROKEAHA.116.012995
Sun Y, Jin K, Xie L et al (2003) VEGF-induced neuroprotection, neurogenesis, and angiogenesis after focal cerebral ischemia. J Clin Invest 111(12):1843–1851. https://doi.org/10.1172/JCI17977
Sutsko RP, Young KC, Ribeiro A et al (2013) Long-term reparative effects of mesenchymal stem cell therapy following neonatal hyperoxia-induced lung injury. Pediatr Res 73(1):46–53. https://doi.org/10.1038/pr.2012.152
Tan CY, Lai RC, Wong W et al (2014) Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models. Stem Cell Res Ther 5(3):76. https://doi.org/10.1186/scrt465
Teixeira FG, Carvalho MM, Sousa N et al (2013) Mesenchymal stem cells secretome: a new paradigm for central nervous system regeneration? Cell Mol Life Sci 70(20):3871–3882. https://doi.org/10.1007/s00018-013-1290-8
Teixeira FG, Carvalho MM, Neves-Carvalho A et al (2015) Secretome of mesenchymal progenitors from the umbilical cord acts as modulator of neural/glial proliferation and differentiation. Stem Cell Rev Rep 11(2):288–297. https://doi.org/10.1007/s12015-014-9576-2
Teixeira FG, Carvalho MM, Panchalingam KM et al (2017) Impact of the secretome of human mesenchymal stem cells on brain structure and animal behavior in a rat model of Parkinson’s disease. Stem Cells Transl Med 6(2):634–646. https://doi.org/10.5966/sctm.2016-0071
Teo GS, Ankrum JA, Martinelli R et al (2012) Mesenchymal stem cells transmigrate between and directly through tumor necrosis factor-α-activated endothelial cells via both leukocyte-like and novel mechanisms. Stem Cells 30(11):2472–2486. https://doi.org/10.1002/stem.1198
The Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA et al (2000) Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342(18):1301–1308. https://doi.org/10.1056/NEJM200005043421801
Timmers L, Lim SK, Arslan F et al (2007) Reduction of myocardial infarct size by human mesenchymal stem cell conditioned medium. Stem Cell Res 1(2):129–137. https://doi.org/10.1016/j.scr.2008.02.002
Tögel FE, Westenfelder C (2010) Mesenchymal stem cells: a new therapeutic tool for AKI. Nat Rev Nephrol 6(3):179–183. https://doi.org/10.1038/nrneph.2009.229
Tögel FE, Westenfelder C (2012) Kidney protection and regeneration following acute injury: progress through stem cell therapy. Am J Kidney Dis 60(6):1012–1022. https://doi.org/10.1053/j.ajkd.2012.08.034
Tögel F, Hu ZM, Weiss K et al (2005) Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 289(1):F31–F42. https://doi.org/10.1152/ajprenal.00007.2005
Toyama K, Honmou O, Harada K et al (2009) Therapeutic benefits of angiogenetic gene-modified human mesenchymal stem cells after cerebral ischemia. Exp Neurol 216(1):47–55. https://doi.org/10.1016/j.expneurol.2008.11.010
Toyoshima A, Yasuhara T, Kameda M et al (2015) Intra-arterial transplantation of allogeneic mesenchymal stem cells mounts neuroprotective effects in a transient ischemic stroke model in rats: analyses of therapeutic time window and its mechanisms. PLoS One 10(6):e0127302. https://doi.org/10.1371/journal.pone.0127302
Tropea KA, Leder E, Aslam M et al (2012) Bronchoalveolar stem cells increase after mesenchymal stromal cell treatment in a mouse model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 302(9):L829–L837. https://doi.org/10.1152/ajplung.00347.2011
Vasandan AB, Jahnavi S, Shashank C et al (2016) Human mesenchymal stem cells program macrophage plasticity by altering their metabolic status via a PGE2-dependent mechanism. Sci Rep 6:38308. https://doi.org/10.1038/srep38308
Venkatachalam MA, Griffin KA, Lan RP et al (2010) Acute kidney injury: a springboard for progression in chronic kidney disease. Am J Physiol Renal Physiol 298(5):F1078–F1094. https://doi.org/10.1152/ajprenal.00017.2010
Vishnubhatla I, Corteling R, Stevanato L et al (2014) The development of stem cell-derived exosomes as a cell-free regenerative medicine. J Circ Biomark 3:2. https://doi.org/10.5772/58597
Wagers AJ, Sherwood RI, Christensen JL et al (2002) Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 297(5590):2256–2259. https://doi.org/10.1126/science.1074807
Wakabayashi K, Nagai A, Sheikh AM 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(5):1017–1025. https://doi.org/10.1002/jnr.22279
Wang F, Yasuhara T, Shingo T et al (2010) Intravenous administration of mesenchymal stem cells exerts therapeutic effects on parkinsonian model of rats: focusing on neuroprotective effects of stromal cell-derived factor-1α. BMC Neurosci 11:52. https://doi.org/10.1186/1471-2202-11-52
Wang S, Guo L, Ge J et al (2015) Excess integrins cause lung entrapment of mesenchymal stem cells. Stem Cells 33(11):3315–3326. https://doi.org/10.1002/stem.2087
Ware LB, Matthay MA (2000) The acute respiratory distress syndrome. N Engl J Med 342(18):1334–1349. https://doi.org/10.1056/NEJM200005043421806
Waszak P, Alphonse R, Vadivel A et al (2012) Preconditioning enhances the paracrine effect of mesenchymal stem cells in preventing oxygen-induced neonatal lung injury in rats. Stem Cells Dev 21(15):2789–2797. https://doi.org/10.1089/scd.2010.0566
Watt FM, Hogan BL (2000) Out of eden: stem cells and their niches. Science 287(5457):1427–1430. https://doi.org/10.1126/science.287.5457.142
Weiss ML, Medicetty S, Bledsoe AR et al (2006) Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson’s disease. Stem Cells 24(3):781–792. https://doi.org/10.1634/stemcells.2005-0330
Wiedemann HP, Wheeler AP, Bernard GR et al (2006) Comparison of two fluid-management strategies in acute lung injury. N Engl J Med 354(24):2564–2575. https://doi.org/10.1056/NEJMoa062200
Wilson JG, Liu KD, Zhuo H et al (2015) Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med 3(1):24–32. https://doi.org/10.1016/S2213-2600(14)70291-7
World Health Organisation (2014) Global status report on non-communicable diseases. Report. World Health Organisation, Geneva. ISBN 978 92 4 156485 4
Xia J, Minamino S, Kuwabara K et al (2019) Stem cell secretome as a new booster for regenerative medicine. Biosci Trends 13(4):299–307. https://doi.org/10.5582/bst.2019.01226
Xin H, Li Y, Cui Y et al (2013a) Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab 33(11):1711–1715. https://doi.org/10.1038/jcbfm.2013.152
Xin H, Li Y, Liu Z et al (2013b) MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles. Stem Cells 31(12):2737–2746. https://doi.org/10.1002/stem.1409
Xin H, Katakowski M, Wang F et al (2017a) MicroRNA-17-92 cluster in exosomes enhance neuroplasticity and functional recovery after stroke in rats. Stroke 48(5):747–753. https://doi.org/10.1161/STROKEAHA.116.015204
Xin H, Wang F, Li Y et al (2017b) Secondary release of exosomes from astrocytes contributes to the increase in neural plasticity and improvement of functional recovery after stroke in rats treated with exosomes harvested from MicroRNA 133b-overexpressing multipotent mesenchymal stromal cells. Cell Transplant 26(2):243–257. https://doi.org/10.3727/096368916X693031
Xu X, Li D, Li X et al (2017) Mesenchymal stem cell conditioned medium alleviates oxidative stress injury induced by hydrogen peroxide via regulating miR143 and its target protein in hepatocytes. BMC Immunol 18(1):51. https://doi.org/10.1186/s12865-017-0232-x
Yalvaç ME, Yarat A, Mercan D et al (2013) Characterization of the secretome of human tooth germ stem cells (hTGSCs) reveals neuro-protection by fine-tuning microenvironment. Brain Behav Immun 32:122–130. https://doi.org/10.1016/j.bbi.2013.03.007
Yan Y, Jiang WQ, Tan YW et al (2017) hucMSC exosome-derived GPX1 is required for the recovery of hepatic oxidant injury. Mol Ther 25(2):465–479. https://doi.org/10.1016/j.ymthe.2016.11.019
Yang D, Wang W, Li L et al (2013) The relative contribution of paracrine effect versus direct differentiation on adipose-derived stem cell transplantation mediated cardiac repair. PLoS One 8(3):e59020. https://doi.org/10.1371/journal.pone.0059020
Yao Y, Huang C, Gu P et al (2016) Combined MSC-secreted factors and neural stem cell transplantation promote functional recovery of PD rats. Cell Transplant 25(6):1101–1113. https://doi.org/10.3727/096368915X689938
Yasuhara T, Matsukawa N, Hara K et al (2006) Transplantation of human neural stem cells exerts neuroprotection in a rat model of Parkinson’s disease. J Neurosci 26(48):12497–12511. https://doi.org/10.1523/JNEUROSCI.3719-06.2006
Zagoura DS, Roubelakis MG, Bitsika V et al (2012) Therapeutic potential of a distinct population of human amniotic fluid mesenchymal stem cells and their secreted molecules in mice with acute hepatic failure. Gut 61(6):894–906. https://doi.org/10.1136/gutjnl-2011-300908
Zhang ZG, Chopp M (2016) Exosomes in stroke pathogenesis and therapy. J Clin Invest 126(4):1190–1197. https://doi.org/10.1172/JCI81133
Zhang ZG, Zhang L, Jiang Q et al (2000) VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest 106(7):829–838. https://doi.org/10.1172/JCI9369
Zhang J, Park ES, Park HJ et al (2019) Apoptosis signal regulating kinase 1 deletion mitigates alpha-synuclein pre-formed fibril propagation in mice. Neurobiol Aging 85:49–57. https://doi.org/10.1016/j.neurobiolaging.2019.09.012
Zhao LR, Duan WM, Reyes M et al (2002) Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Exp Neurol 174(1):11–20. https://doi.org/10.1006/exnr.2001.7853
Zhao MZ, Nonoguchi N, Ikeda N et al (2006) Novel therapeutic strategy for stroke in rats by bone marrow stromal cells and ex vivo HGF gene transfer with HSV-1 vector. J Cereb Blood Flow Metab 26(9):1176–1188. https://doi.org/10.1038/sj.jcbfm.9600273
Zheng G, Huang L, Tong H et al (2014) Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study. Respir Res 15(1):39. https://doi.org/10.1186/1465-9921-15-39
Zhou BR, Zhang T, Bin Jameel AA et al (2016) The efficacy of conditioned media of adipose-derived stem cells combined with ablative carbon dioxide fractional resurfacing for atrophic acne scars and skin rejuvenation. J Cosmet Laser Ther 18(3):138–148. https://doi.org/10.3109/14764172.2015.1114638
Zhou L, Lin Q, Wang P et al (2017) Enhanced neuroprotective efficacy of bone marrow mesenchymal stem cells co-overexpressing BDNF and VEGF in a rat model of cardiac arrest-induced global cerebral ischemia. Cell Death Dis 8(5):e2774. https://doi.org/10.1038/cddis.2017.184
Zhu YG, Feng XM, Abbott J et al (2014) Human mesenchymal stem cell microvesicles for treatment of Escherichia coli endotoxin-induced acute lung injury in mice. Stem Cells 32(1):116–125. https://doi.org/10.1002/stem.1504
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2021 The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd.
About this chapter
Cite this chapter
Xia, J., Arai, S., Haider, K.H. (2021). Researches and Applications of Stem Cell Secretome. In: Haider, K.H. (eds) Stem cells: From Potential to Promise. Springer, Singapore. https://doi.org/10.1007/978-981-16-0301-3_7
Download citation
DOI: https://doi.org/10.1007/978-981-16-0301-3_7
Published:
Publisher Name: Springer, Singapore
Print ISBN: 978-981-16-0300-6
Online ISBN: 978-981-16-0301-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)