277
Views
5
CrossRef citations to date
0
Altmetric
Review

Mechanism of Action of Mesenchymal Stem Cells (MSCs): impact of delivery method

ORCID Icon, ORCID Icon, ORCID Icon & ORCID Icon
Pages 449-463 | Received 30 Mar 2021, Accepted 07 Dec 2021, Published online: 27 Dec 2021

References

  • Charbord P. Bone marrow mesenchymal stem cells: historical overview and concepts. Hum Gene Ther. 2010 Sep;21(9):1045–1056.
  • Strioga M, Viswanathan S, Darinskas A, et al. Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev. 2012 Sep 20; 21(14):2724–2752.
  • Pelekanos RA, Sardesai VS, Futrega K, et al. Isolation and expansion of mesenchymal stem/stromal cells derived from human placenta tissue. J Vis Exp. 2016 Jun;6(112):54204. doi:https://doi.org/10.3791/54204.
  • Sharpe PT. Dental mesenchymal stem cells. Development. 2016 Jul 1; 143(13):2273–2280.
  • Lee OK, Kuo TK, Chen WM, et al. Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood. 2004 Mar 1; 103(5):1669–1675.
  • Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. the international society for cellular therapy position statement. Cytotherapy. 2006;8(4):315–317.
  • Pires AO, Mendes-Pinheiro B, Teixeira FG, et al. Unveiling the differences of secretome of human bone marrow mesenchymal stem cells, adipose tissue-derived stem cells, and human umbilical cord perivascular cells: a proteomic analysis. Stem Cells Dev. 2016 Jul 15 25(14):1073–1083.
  • Shi Y, Wang Y, Li Q, et al. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nat Rev Nephrol. 2018 Aug;14(8):493–507.
  • Kanelidis AJ, Premer C, Lopez J, et al. Route of delivery modulates the efficacy of mesenchymal stem cell therapy for myocardial infarction: a meta-analysis of preclinical studies and clinical trials. Circ Res. 2017 Mar 31 ; 120(7):1139–1150.
  • Leibacher J, Henschler R. Biodistribution, migration and homing of systemically applied mesenchymal stem/stromal cells. Stem Cell Res Ther. 2016 Jan 11; 7:7.
  • Li J, Hu S, Zhu D, et al. All roads lead to Rome (the Heart): cell retention and outcomes from various delivery routes of cell therapy products to the heart. J Am Heart Assoc. 2021 Apr 20 10(8):e020402.
  • Xie C, Yang Z, Suo Y, et al. systemically infused mesenchymal stem cells show different homing profiles in healthy and tumor mouse models. Stem Cells Transl Med. 2017 Apr;6(4):1120–1131.
  • Luger D, Lipinski MJ, Westman PC, et al. Intravenously delivered mesenchymal stem cells: systemic anti-inflammatory effects improve left ventricular dysfunction in acute myocardial infarction and ischemic cardiomyopathy. Circ Res. 2017 May 12 120(10):1598–1613.
  • Pittenger MF, Discher DE, Peault BM, et al. Mesenchymal stem cell perspective: cell biology to clinical progress. NPJ Regen Med. 2019;4:22.
  • De Becker A, Riet IV. Homing and migration of mesenchymal stromal cells: how to improve the efficacy of cell therapy? World J Stem Cells. 2016 Mar 26; 8(3):73–87.
  • Zhang Q, Nguyen P, Xu Q, et al. Neural progenitor-like cells induced from human gingiva-derived mesenchymal stem cells regulate myelination of schwann cells in rat sciatic nerve regeneration. Stem Cells Transl Med. 2017 Feb;6(2):458–470.
  • Ueda N, Atsuta I, Ayukawa Y, et al. Novel application method for mesenchymal stem cell therapy utilizing its attractant-responsive accumulation property. Appl Sci-Basel. 2019 Nov 2;9(22):4908.
  • Masterson CH, Tabuchi A, Hogan G, et al. Intra-vital imaging of mesenchymal stromal cell kinetics in the pulmonary vasculature during infection. Sci Rep. 2021 Mar 4 11(1):5265.
  • Hoogduijn MJ, Roemeling-van Rhijn M, Engela AU, et al. Mesenchymal stem cells induce an inflammatory response after intravenous infusion. Stem Cells Dev. 2013 Nov 1 22(21):2825–2835.
  • Liu Z, Mikrani R, Zubair HM, et al. Systemic and local delivery of mesenchymal stem cells for heart renovation: challenges and innovations. Eur J Pharmacol. 2020 Jun 5;876:173049.
  • Watanabe M, Yavagal DR. Intra-arterial delivery of mesenchymal stem cells. Brain Circ. 2016 Jul-Sep;2(3):114–117.
  • Yavagal DR, Lin B, Raval AP, et al. Efficacy and dose-dependent safety of intra-arterial delivery of mesenchymal stem cells in a rodent stroke model. PloS One. 2014;9(5):e93735.
  • Argibay B, Trekker J, Himmelreich U, et al. Intraarterial route increases the risk of cerebral lesions after mesenchymal cell administration in animal model of ischemia. Sci Rep. 2017 Jan 16 7:40758.
  • Guzman R, Janowski M, Walczak P. Intra-arterial delivery of cell therapies for stroke. Stroke. 2018 May;49(5):1075–1082.
  • Sarmah D, Agrawal V, Rane P, et al. Mesenchymal stem cell therapy in ischemic stroke: a meta-analysis of preclinical studies. Clin Pharmacol Ther. 2018 Jun;103(6):990–998.
  • Suk KT, Yoon JH, Kim MY, et al. Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: phase 2 trial. Hepatology. 2016 Dec;64(6):2185–2197.
  • Saad A, Dietz AB, Herrmann SMS, et al. Autologous mesenchymal stem cells increase cortical perfusion in renovascular disease. J Am Soc Nephrol. 2017 Sep;28(9):2777–2785.
  • Bazhanov N, Ylostalo JH, Bartosh TJ, et al. Intraperitoneally infused human mesenchymal stem cells form aggregates with mouse immune cells and attach to peritoneal organs. Stem Cell Res Ther. 2016 Feb 10 7:27.
  • Nam Y, Jung SM, Rim YA, et al. Intraperitoneal infusion of mesenchymal stem cell attenuates severity of collagen antibody induced arthritis. PLoS One. 2018;13(6):e0198740.
  • Lee RH, Pulin AA, Seo MJ, et al. Intravenous hMSCs improve myocardial infarction in mice because cells embolized in lung are activated to secrete the anti-inflammatory protein TSG-6. Cell Stem Cell. 2009 Jul 2 5(1):54–63.
  • Wang M, Liang C, Hu H, et al. Intraperitoneal injection (IP), Intravenous injection (IV) or anal injection (AI)? Best way for mesenchymal stem cells transplantation for colitis. Sci Rep. 2016 Aug 4 6:30696.
  • Ezquer M, Urzua CA, Montecino S, et al. Intravitreal administration of multipotent mesenchymal stromal cells triggers a cytoprotective microenvironment in the retina of diabetic mice. Stem Cell Res Ther. 2016 Mar 16; 7:42.
  • Petrella F, Spaggiari L, Acocella F, et al. Airway fistula closure after stem-cell infusion. N Engl J Med. 2015 Jan 1 372(1):96–97.
  • Qazi TH, Duda GN, Ort MJ, et al. Cell therapy to improve regeneration of skeletal muscle injuries. J Cachexia Sarcopenia Muscle. 2019 Jun;10(3):501–516.
  • Himeoka Y, Kaneko K. Enzyme oscillation can enhance the thermodynamic efficiency of cellular metabolism: consequence of anti-phase coupling between reaction flux and affinity. Phys Biol. 2016 Apr 5; 13(2):026002.
  • van Den Akker F, Feyen DAM, van Den Hoogen P, et al. Intramyocardial stem cell injection: go(ne) with the flow. Eur Heart J. 2017 Jan 14 38(3):184–186.
  • Li H, Rong P, Ma X, et al. Paracrine effect of mesenchymal stem cell as a novel therapeutic strategy for diabetic nephropathy. Life Sci. 2018 Dec 15;215:113–118.
  • Fiore EJ, Dominguez LM, Bayo J, et al. Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: cells and extracellular vesicles as therapeutic strategies. World J Gastroenterol. 2018 Jun 21; 24(23):2427–2440.
  • Leuning DG, Beijer NRM, Du Fosse NA, et al. The cytokine secretion profile of mesenchymal stromal cells is determined by surface structure of the microenvironment. Sci Rep. 2018 May 16 8(1):7716.
  • Patananan AN, Sercel AJ, Wu TH, et al. Pressure-driven mitochondrial transfer pipeline generates mammalian cells of desired genetic combinations and fates. Cell Rep. 2020 Dec 29 33(13):108562.
  • Ullah M, Liu DD, Thakor AS. Mesenchymal stromal cell homing: mechanisms and strategies for improvement. iScience. 2019 May 31; 15:421–438
  • Weiss ARR, Dahlke MH. Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs. Front Immunol. 2019;10:1191.
  • Pan BT, Teng K, Wu C, et al. Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes. J Cell Biol. 1985 Sep;101(3):942–948.
  • Plotnikov EY, Khryapenkova TG, Vasileva AK, et al. Cell-to-cell cross-talk between mesenchymal stem cells and cardiomyocytes in co-culture. J Cell Mol Med. 2008 Sep-Oct;12(5A):1622–1631.
  • Da Cunha F F, Andrade-Oliveira V, de Almeida D C, et al. Extracellular vesicles isolated from mesenchymal stromal cells modulate CD4(+) T lymphocytes toward a regulatory profile. Cells. 2020 Apr 23;9(4). https://doi.org/10.3390/cells9041059.
  • Xia X, Chan KF, Wong GTY, et al. Mesenchymal stem cells promote healing of nonsteroidal anti-inflammatory drug-related peptic ulcer through paracrine actions in pigs. Sci Transl Med. 2019 Oct 30;11(516). https://doi.org/10.1126/scitranslmed.aat7455.
  • Zriek F, Di Battista JA, Alaaeddine N. Mesenchymal stromal cell secretome: immunomodulation, tissue repair and effects on neurodegenerative conditions. Curr Stem Cell Res Ther. 2021 Feb 2; 16(6):656–669.
  • Shin S, Lee J, Kwon Y, et al. Comparative proteomic analysis of the mesenchymal stem cells secretome from adipose, bone marrow, placenta and wharton’s jelly. Int J Mol Sci. 2021 Jan 15 22(2):845.
  • Trzyna A, Banas-Zabczyk A. Adipose-derived stem cells secretome and its potential application in “stem cell-free therapy.” Biomolecules. 2021 Jun 13; 11(6):878.
  • Donders R, Bogie JFJ, Ravanidis S, et al. Human Wharton’s Jelly-derived stem cells display a distinct immunomodulatory and proregenerative transcriptional signature compared to bone marrow-derived stem cells. Stem Cells Dev. 2018 Jan 15 27(2):65–84.
  • Park KS, Bandeira E, Shelke GV, et al. Enhancement of therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. Stem Cell Res Ther. 2019 Sep 23; 10(1):288.
  • Karantalis V, Suncion-Loescher VY, Bagno L, et al. Synergistic effects of combined cell therapy for chronic ischemic cardiomyopathy. J Am Coll Cardiol. 2015 Nov 3 66(18):1990–1999.
  • Zhang Z, Yang J, Yan W, et al. Pretreatment of cardiac stem cells with exosomes derived from mesenchymal stem cells enhances myocardial repair. J Am Heart Assoc. 2016 Jan 25;5(1). https://doi.org/10.1161/JAHA.115.002856
  • Ikeda G, Santoso MR, Tada Y, et al. Mitochondria-rich extracellular vesicles from autologous stem cell-derived cardiomyocytes restore energetics of ischemic myocardium. J Am Coll Cardiol. 2021 Mar 2 77(8):1073–1088.
  • Phinney DG, Pittenger MF. Concise Review: MSC-derived exosomes for cell-free therapy. Stem Cells. 2017 Apr;35(4):851–858.
  • Fisher SA, Doree C, Mathur A, et al. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev 2016 Dec 24;12: CD007888. https://doi.org/10.1002/14651858.CD007888.pub3
  • Gupta A, Cady C, Fauser AM, et al. Cell-free stem cell-derived extract formulation for regenerative medicine applications. Int J Mol Sci. 2020 Dec 9 21(24):9364.
  • Sung DK, Chang YS, Ahn SY, et al. Optimal route for human umbilical cord blood-derived mesenchymal stem cell transplantation to protect against neonatal hyperoxic lung injury: gene expression profiles and histopathology. PLoS One. 2015;10(8):e0135574.
  • Doorn J, Moll G, Le Blanc K, et al. Therapeutic applications of mesenchymal stromal cells: paracrine effects and potential improvements. Tissue Eng Part B Rev. 2012 Apr;18(2):101–115.
  • Park WS, Ahn SY, Sung SI, et al. Strategies to enhance paracrine potency of transplanted mesenchymal stem cells in intractable neonatal disorders. Pediatr Res. 2018 Jan;83(1–2):214–222.
  • Karantalis V, DiFede DL, Gerstenblith G, et al. Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: the Prospective Randomized Study of Mesenchymal Stem Cell Therapy in Patients Undergoing Cardiac Surgery (PROMETHEUS) trial. Circ Res. 2014 Apr 11 114(8):1302–1310.
  • Wehman B, Sharma S, Pietris N, et al. Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload. Am J Physiol Heart Circ Physiol. 2016 Jun 1 310(11):H1816–26.
  • Hatzistergos KE, Williams AR, Dykxhoorn D, et al. Tumor suppressors RB1 and CDKN2a Cooperatively regulate cell-cycle progression and differentiation during cardiomyocyte development and repair. Circ Res. 2019 Apr 12; 124(8):1184–1197.
  • Shabbir A, Cox A, Rodriguez-Menocal L, et al. Mesenchymal stem cell exosomes induce proliferation and migration of normal and chronic wound fibroblasts, and enhance angiogenesis in vitro. Stem Cells Dev. 2015 Jul 15; 24(14):1635–1647.
  • Vrijsen KR, Maring JA, Chamuleau SA, et al. Exosomes from cardiomyocyte progenitor cells and mesenchymal stem cells stimulate angiogenesis via EMMPRIN. Adv Healthc Mater. 2016 Oct;5(19):2555–2565.
  • Yao Y, Huang J, Geng Y, et al. Paracrine action of mesenchymal stem cells revealed by single cell gene profiling in infarcted murine hearts. PLoS One. 2015;10(6):e0129164.
  • Mayourian J, Cashman TJ, Ceholski DK, et al. Experimental and computational insight into human mesenchymal stem cell paracrine signaling and heterocellular coupling effects on cardiac contractility and arrhythmogenicity. Circ Res. 2017 Aug 4 121(4):411–423.
  • Bagno L, Hatzistergos KE, Balkan W, et al. Mesenchymal stem cell-based therapy for cardiovascular disease: progress and challenges. Mol Ther. 2018 Jul 5; 26(7):1610–1623.
  • Paliwal S, Chaudhuri R, Agrawal A, et al. Regenerative abilities of mesenchymal stem cells through mitochondrial transfer. J Biomed Sci. 2018 Mar 30; 25(1):31.
  • Ahmad T, Mukherjee S, Pattnaik B, et al. Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy. EMBO J. 2014 May 2 33(9):994–1010.
  • Zhang Y, Yu Z, Jiang D, et al. iPSC-MSCs with high intrinsic miro1 and sensitivity to TNF-alpha yield efficacious mitochondrial transfer to rescue anthracycline-induced cardiomyopathy. Stem Cell Reports. 2016 Oct 11 7(4):749–763.
  • Mahrouf-Yorgov M, Augeul L, Da Silva CC, et al. Mesenchymal stem cells sense mitochondria released from damaged cells as danger signals to activate their rescue properties. Cell Death Differ. 2017 Jul;24(7):1224–1238.
  • Han H, Hu J, Yan Q, et al. Bone marrow-derived mesenchymal stem cells rescue injured H9c2 cells via transferring intact mitochondria through tunneling nanotubes in an in vitro simulated ischemia/reperfusion model. Mol Med Rep. 2016 Feb;13(2):1517–1524.
  • Zhu H, Yu B, Yang L. Exogenous and endogenous stem cells for skeletal regeneration. Stem Cells Int. 2018;2018:2574243.
  • Raicevic G, Najar M, Najimi M, et al. Influence of inflammation on the immunological profile of adult-derived human liver mesenchymal stromal cells and stellate cells. Cytotherapy. 2015 Feb;17(2):174–185.
  • Berglund AK, Fortier LA, Antczak DF, et al. Immunoprivileged no more: measuring the immunogenicity of allogeneic adult mesenchymal stem cells. Stem Cell Res Ther. 2017 Dec 22; 8(1):288.
  • Golpanian S, Wolf A, Hatzistergos KE, et al. Rebuilding the damaged heart: mesenchymal stem cells, cell-based therapy, and engineered heart tissue. Physiol Rev. 2016 Jul;96(3):1127–1168.
  • Hare JM, DiFede DL, Rieger AC, et al. Randomized comparison of allogeneic versus autologous mesenchymal stem cells for nonischemic dilated cardiomyopathy: POSEIDON-DCM trial. J Am Coll Cardiol. 2017 Feb 07 69(5):526–537.
  • Caplan H, Olson SD, Kumar A, et al. Mesenchymal stromal cell therapeutic delivery: translational challenges to clinical application. Front Immunol. 2019;10:1645.
  • Guo J, Lin GS, Bao CY, et al. Anti-inflammation role for mesenchymal stem cells transplantation in myocardial infarction. Inflammation. 2007 Aug;30(3–4):97–104.
  • Ohnishi S, Yanagawa B, Tanaka K, et al. Transplantation of mesenchymal stem cells attenuates myocardial injury and dysfunction in a rat model of acute myocarditis. J Mol Cell Cardiol. 2007 Jan;42(1):88–97.
  • Lee RH, Yu JM, Foskett AM, et al. TSG-6 as a biomarker to predict efficacy of human mesenchymal stem/progenitor cells (hMSCs) in modulating sterile inflammation in vivo. Proc Natl Acad Sci U S A. 2014 Nov 25 111(47):16766–16771.
  • Hamidian Jahromi S, Estrada C, Li Y, et al. Human umbilical cord perivascular cells and human bone marrow mesenchymal stromal cells transplanted intramuscularly respond to a distant source of inflammation. Stem Cells Dev. 2018 Mar 15; 27(6):415–429.
  • Zhang L, Dang RJ, Li H, et al. SOCS1 regulates the immune modulatory properties of mesenchymal stem cells by inhibiting nitric oxide production. PLoS One. 2014;9(5):e97256.
  • Chen L, Zhang Y, Tao L, et al. Mesenchymal stem cells with eNOS over-expression enhance cardiac repair in rats with myocardial infarction. Cardiovasc Drugs Ther. 2017 Feb;31(1):9–18.
  • Maria ATJ, Rozier P, Fonteneau G, et al. iNOS activity is required for the therapeutic effect of mesenchymal stem cells in experimental systemic sclerosis. Front Immunol. 2018;9:3056.
  • Guo Y, Yu Y, Hu S, et al. The therapeutic potential of mesenchymal stem cells for cardiovascular diseases. Cell Death Dis. 2020 May 11; 11(5):349.
  • Golpanian S, DiFede DL, Khan A, et al. Allogeneic human mesenchymal stem cell infusions for aging frailty. J Gerontol A Biol Sci Med Sci. [2017 Oct 12];72(11):1505–1512.
  • Florea V, Rieger AC, DiFede DL, et al. Dose comparison study of allogeneic mesenchymal stem cells in patients with ischemic cardiomyopathy (The TRIDENT Study). Circ Res. 2017 Nov 10 121(11):1279–1290.
  • Khodayari S, Khodayari H, Amiri AZ, et al. Inflammatory microenvironment of acute myocardial infarction prevents regeneration of heart with stem cells therapy. Cell Physiol Biochem. 2019;53(5):887–909.
  • Waterman RS, Tomchuck SL, Henkle SL, et al. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype. PLoS One. 2010 Apr 26; 5(4):e10088.
  • Deng D, Zhang P, Guo Y, et al. A randomised double-blind, placebo-controlled trial of allogeneic umbilical cord-derived mesenchymal stem cell for lupus nephritis. Ann Rheum Dis. 2017 Aug;76(8):1436–1439.
  • Garcia-Olmo D, Schwartz DA. Cumulative evidence that mesenchymal stem cells promote healing of perianal fistulas of patients with crohn’s disease–going from bench to bedside. Gastroenterology. 2015 Oct;149(4):853–857.
  • Zha S, Tay JC, Zhu S, et al. Generation of mesenchymal stromal cells with low immunogenicity from Human PBMC-Derived beta2 microglobulin knockout induced pluripotent stem cells. Cell Transplant. 2020 Jan-Dec;29:963689720965529.
  • Meng X, Zheng M, Yu M, et al. Transplantation of CRISPRa system engineered IL10-overexpressing bone marrow-derived mesenchymal stem cells for the treatment of myocardial infarction in diabetic mice. J Biol Eng. 2019;13(1):49.
  • Nitzsche F, Muller C, Lukomska B, et al. Concise review: MSC adhesion cascade-insights into homing and transendothelial migration. Stem Cells. 2017 Jun;35(6):1446–1460.
  • Madl CM, Heilshorn SC, Blau HM. Bioengineering strategies to accelerate stem cell therapeutics. Nature. 2018 May;557(7705):335–342.
  • Hu X, Yu SP, Fraser JL, et al. Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. J Thorac Cardiovasc Surg. 2008 Apr;135(4):799–808.
  • Wu Z, Chen G, Zhang J, et al. Treatment of myocardial infarction with gene-modified mesenchymal stem cells in a small molecular hydrogel. Sci Rep. 2017 Nov 20 7(1):15826.
  • Levy O, Kuai R, Siren EMJ, et al. Shattering barriers toward clinically meaningful MSC therapies. Sci Adv. 2020 Jul;6(30):eaba6884.
  • Park SJ, Kim RY, Park BW, et al. Dual stem cell therapy synergistically improves cardiac function and vascular regeneration following myocardial infarction. Nat Commun. 2019 Jul 16 10(1):3123.
  • Golchin A, Shams F, Karami F. Advancing mesenchymal stem cell therapy with CRISPR/Cas9 for clinical trial studies. Adv Exp Med Biol. 2020;1247:89–100.
  • Tilokee EL, Latham N, Jackson R, et al. Paracrine engineering of human explant-derived cardiac stem cells to over-express stromal-cell derived factor 1alpha enhances myocardial repair. Stem Cells. 2016 Jul;34(7):1826–1835.
  • Kulandavelu S, Balkan W, Hare JM. Next-Generation stem cell therapy: genetically modified mesenchymal stem cells for cardiac repair: editorial to: “mesenchymal stem cells with enos over-expression enhance cardiac repair in rats with myocardial infarction” by Leilei Chen et al. Cardiovasc Drugs Ther. 2017 Feb;31(1):5–7.
  • Vishnubalaji R, Elango R, Al-Toub M, et al. Neoplastic transformation of human mesenchymal stromal cells mediated via LIN28B. Sci Rep. 2019 May 30 9(1):8101.
  • Lacerda L, Debeb BG, Smith D, et al. Mesenchymal stem cells mediate the clinical phenotype of inflammatory breast cancer in a preclinical model. Breast Cancer Res. 2015 Mar 20 17(1):42.
  • Guess AJ, Daneault B, Wang R, et al. Safety profile of good manufacturing practice manufactured interferon gamma-primed mesenchymal stem/stromal cells for clinical trials. Stem Cells Transl Med. 2017 Oct;6(10):1868–1879.
  • Niess H, Von Einem JC, Thomas MN, et al. Treatment of advanced gastrointestinal tumors with genetically modified autologous mesenchymal stromal cells (TREAT-ME1): study protocol of a phase I/II clinical trial. BMC Cancer. 2015 Apr 8 15(1):237.
  • Ouyang X, Wang X, Kraatz HB, et al. A trojan horse biomimetic delivery strategy using mesenchymal stem cells for PDT/PTT therapy against lung melanoma metastasis. Biomater Sci. 2020 Feb 21 8(4):1160–1170.
  • Niess H, Thomas MN, Schiergens TS, et al. Genetic engineering of mesenchymal stromal cells for cancer therapy: turning partners in crime into Trojan horses. Innov Surg Sci. 2016 Sep;1(1):19–32.
  • Moll G, Ankrum JA, Kamhieh-Milz J, et al. Intravascular mesenchymal stromal/stem cell therapy product diversification: time for new clinical guidelines. Trends Mol Med. 2019 Feb;25(2):149–163.
  • Vu Q, Xie K, Eckert M, et al. Meta-analysis of preclinical studies of mesenchymal stromal cells for ischemic stroke. Neurology. 2014 Apr 8; 82(14):1277–1286.
  • Terashvili M, Bosnjak ZJ. Stem cell therapies in cardiovascular disease. J Cardiothorac Vasc Anesth. 2019 Jan;33(1):209–222.
  • Schuleri KH, Amado LC, Boyle AJ, et al. Early improvement in cardiac tissue perfusion due to mesenchymal stem cells. Am J Physiol Heart Circ Physiol. 2008 May;294(5):H2002–11.
  • Hatzistergos KE, Quevedo H, Oskouei BN, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res. 2010 Oct 1 107(7):913–922.
  • Rodrigo SF, van Ramshorst J, Hoogslag GE, et al. Intramyocardial injection of autologous bone marrow-derived ex vivo expanded mesenchymal stem cells in acute myocardial infarction patients is feasible and safe up to 5 years of follow-up. J Cardiovasc Transl Res. 2013 Oct;6(5):816–825.
  • Guo Y, Peng Y, Zeng H, et al. Progress in mesenchymal stem cell therapy for ischemic stroke. Stem Cells Int. 2021;2021:9923566.
  • Ding DC, Shyu WC, Chiang MF, et al. Enhancement of neuroplasticity through upregulation of beta1-integrin in human umbilical cord-derived stromal cell implanted stroke model. Neurobiol Dis. 2007 Sep;27(3):339–353.
  • Guo ZY, Sun X, Xu XL, et al. Human umbilical cord mesenchymal stem cells promote peripheral nerve repair via paracrine mechanisms. Neural Regen Res. 2015 Apr;10(4):651–658.
  • Zhang Y, Chopp M, Liu XS, et al. Exosomes derived from mesenchymal stromal cells promote axonal growth of cortical neurons. Mol Neurobiol. 2017 May;54(4):2659–2673.
  • Elia CA, Tamborini M, Rasile M, et al. Intracerebral injection of extracellular vesicles from mesenchymal stem cells exerts reduced abeta plaque burden in early stages of a preclinical model of Alzheimer’s Disease. Cells. 2019 Sep 10 8(9):1059.
  • Bodart-Santos V, de Carvalho LRP, de Godoy MA, et al. Extracellular vesicles derived from human Wharton’s jelly mesenchymal stem cells protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid-beta oligomers. Stem Cell Res Ther. 2019 Nov 20 10(1):332.
  • de Godoy MA, Saraiva LM, de Carvalho Lrp, et al. Mesenchymal stem cells and cell-derived extracellular vesicles protect hippocampal neurons from oxidative stress and synapse damage induced by amyloid-beta oligomers. J Biol Chem. 2018 Feb 9 293(6):1957–1975.
  • Cui GH, Wu J, Mou FF, et al. Exosomes derived from hypoxia-preconditioned mesenchymal stromal cells ameliorate cognitive decline by rescuing synaptic dysfunction and regulating inflammatory responses in APP/PS1 mice. FASEB J. 2018 Feb;32(2):654–668.
  • Xin H, Li Y, Liu Z, et al. 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. 2013 Dec;31(12):2737–2746.
  • Zhou J, Wang Y, Liu Y, et al. Adipose derived mesenchymal stem cells alleviated osteoarthritis and chondrocyte apoptosis through autophagy inducing. J Cell Biochem doi:https://doi.org/10.1002/jcb.27530. 2018 Oct 13. Online ahead of print.
  • Toghraie F, Razmkhah M, Gholipour MA, et al. Scaffold-free adipose-derived stem cells (ASCs) improve experimentally induced osteoarthritis in rabbits. Arch Iran Med. 2012 Aug;15(8):495–499.
  • Chahal J, Gomez-Aristizabal A, Shestopaloff K, et al. 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. 2019 Aug;8(8):746–757.
  • Jo CH, Chai JW, Jeong EC, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a 2-Year follow-up study. Am J Sports Med. 2017 Oct;45(12):2774–2783.
  • Gp F, Hb L, Atp S, et al. Cell therapy: effect of locally injected mesenchymal stromal cells derived from bone marrow or adipose tissue on bone regeneration of rat calvarial defects. Sci Rep. 2019 Sep 17 9(1):13476.
  • Sj K, Yw S, Kh Y, et al. A multi-center, randomized, clinical study to compare the effect and safety of autologous cultured osteoblast(Ossron) injection to treat fractures. BMC Musculoskelet Disord. 2009 Feb 12;10:20.
  • Yang Y, Pan Q, Zou K, et al. Administration of allogeneic mesenchymal stem cells in lengthening phase accelerates early bone consolidation in rat distraction osteogenesis model. Stem Cell Res Ther. 2020 Mar 20 11(1):129.
  • Desando G, Cavallo C, Sartoni F, et al. Intra-articular delivery of adipose derived stromal cells attenuates osteoarthritis progression in an experimental rabbit model. Arthritis Res Ther. 2013 Jan 29 15(1):R22.
  • Zhang QZ, Su WR, Shi SH, et al. Human gingiva-derived mesenchymal stem cells elicit polarization of m2 macrophages and enhance cutaneous wound healing. Stem Cells. 2010 Oct;28(10):1856–1868.
  • Satue M, Schuler C, Ginner N, et al. Intra-articularly injected mesenchymal stem cells promote cartilage regeneration, but do not permanently engraft in distant organs. Sci Rep. 2019 Jul 12; 9(1):10153.
  • Migliorini F, Tingart M, Maffulli N. Progress with stem cell therapies for tendon tissue regeneration. Expert Opin Biol Ther. 2020 Nov;20(11):1373–1379.
  • Lee SY, Kim W, Lim C, et al. Treatment of lateral epicondylosis by using allogeneic adipose-derived mesenchymal stem cells: a pilot study. Stem Cells. 2015 Oct;33(10):2995–3005.
  • Hurd JL, Facile TR, Weiss J, et al. Safety and efficacy of treating symptomatic, partial-thickness rotator cuff tears with fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) isolated at the point of care: a prospective, randomized, controlled first-in-human pilot study. J Orthop Surg Res. 2020 Mar 30 15(1):122.
  • Magne B, Lataillade JJ, Trouillas M. Mesenchymal stromal cell preconditioning: the next step toward a customized treatment for severe burn. Stem Cells Dev. 2018 Oct 15; 27(20):1385–1405.
  • Falanga V, Iwamoto S, Chartier M, et al. Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds. Tissue Eng. 2007 Jun;13(6):1299–1312.
  • Zhou Y, Zhao B, Zhang XL, et al. Combined topical and systemic administration with human adipose-derived mesenchymal stem cells (hADSC) and hADSC-derived exosomes markedly promoted cutaneous wound healing and regeneration. Stem Cell Res Ther. 2021 May 1 12(1):257.
  • Hu P, Yang Q, Wang Q, et al. Mesenchymal stromal cells-exosomes: a promising cell-free therapeutic tool for wound healing and cutaneous regeneration. Burns Trauma. 2019;7:38.
  • Hyldig K, Riis S, Pennisi CP, et al. Implications of extracellular matrix production by adipose tissue-derived stem cells for development of Wound healing therapies. Int J Mol Sci. 2017 May 31; 18(6):1167.
  • Lo Sicco C, Reverberi D, Balbi C, et al. Mesenchymal stem cell-derived extracellular vesicles as mediators of anti-inflammatory effects: endorsement of macrophage polarization. Stem Cells Transl Med. 2017 Mar;6(3):1018–1028.
  • Lozito TP, Jackson WM, Nesti LJ, et al. Human mesenchymal stem cells generate a distinct pericellular zone of MMP activities via binding of MMPs and secretion of high levels of TIMPs. Matrix Biol. 2014 Feb;34:132–143.
  • Czarnecka A, Odziomek A, Murzyn M, et al. Wharton’s jelly-derived mesenchymal stem cells in the treatment of four patients with alopecia areata. Adv Clin Exp Med. 2021 Feb;30(2):211–218.
  • Gentile P, Scioli MG, Bielli A, et al. Stem cells from human hair follicles: first mechanical isolation for immediate autologous clinical use in androgenetic alopecia and hair loss. Stem Cell Investig. 2017;4(7):58.
  • Gentile P, Scioli MG, Cervelli V, et al. Autologous micrografts from scalp tissue: trichoscopic and long-term clinical evaluation in male and female androgenetic alopecia. Biomed Res Int. 2020;2020:7397162.
  • Srifa W, Kosaric N, Amorin A, et al. Cas9-AAV6-engineered human mesenchymal stromal cells improved cutaneous wound healing in diabetic mice. Nat Commun. 2020 May 18 11(1):2470.
  • Meng ZW, Baumgart DC. Darvadstrocel for the treatment of perianal fistulas in Crohn’s disease. Expert Rev Gastroenterol Hepatol. 2020 Jun;14(6):405–410.
  • Tompkins BA, DiFede DL, Khan A, et al. Allogeneic mesenchymal stem cells ameliorate aging frailty: a phase ii randomized, double-blind, placebo-controlled clinical trial. J Gerontol A Biol Sci Med Sci. 2017 Oct 12 72(11):1513–1522.
  • Walston J, Robinson TN, Zieman S, et al. Integrating frailty research into the medical specialties-Report from a U13 conference. J Am Geriatr Soc. 2017 Oct;65(10):2134–2139.
  • Florea V, Bagno L, Rieger AC, et al. Attenuation of frailty in older adults with mesenchymal stem cells. Mech Ageing Dev. 2019 Jul;181:47–58.
  • Pahor M, Kritchevsky SB, Waters DL, et al. Designing drug trials for frailty: icfsr task force 2018. J Frailty Aging. 2018;7(3):150–154.
  • Schulman IH, Balkan W, Hare JM. Mesenchymal stem cell therapy for aging frailty. Front Nutr. 2018;5:108.
  • Oliva AA, McClain-Moss L, Pena A, et al. Allogeneic mesenchymal stem cell therapy: a regenerative medicine approach to geroscience. Aging Med (Milton). 2019 Sep;2(3): 142–146.
  • Durand N, Mallea J, Zubair AC. Insights into the use of mesenchymal stem cells in COVID-19 mediated acute respiratory failure. NPJ Regen Med. 2020 Oct 26; 5(1):17.
  • Qu W, Wang Z, Hare JM, et al. Cell-based therapy to reduce mortality from COVID-19: systematic review and meta-analysis of human studies on acute respiratory distress syndrome. Stem Cells Transl Med. 2020 Sep;9(9):1007–1022.
  • Tao J, Nie Y, Wu H, et al. Umbilical cord blood-derived mesenchymal stem cells in treating a critically ill COVID-19 patient. J Infect Dev Ctries. 2020 Oct 31 14(10):1138–1145.
  • Liang B, Chen J, Li T, et al. Clinical remission of a critically ill COVID-19 patient treated by human umbilical cord mesenchymal stem cells: a case report. Medicine (Baltimore). 2020 Jul 31 99(31):e21429.
  • Yilmaz R, Adas G, Cukurova Z, et al. Mesenchymal stem cells treatment in COVID-19 patient with multi-organ involvement. Bratisl Lek Listy. 2020;121(12):847–852.
  • Leng Z, Zhu R, Hou W, et al. Transplantation of ACE2(-) mesenchymal stem cells improves the outcome of patients with COVID-19 Pneumonia. Aging Dis. 2020 Apr;11(2):216–228.
  • Gentile P, Sterodimas A. Adipose stem cells (ASCs) and stromal vascular fraction (SVF) as a potential therapy in combating (COVID-19)-Disease. Aging Dis. 2020 May;11(3):465–469.
  • Gentile P, Sterodimas A, Pizzicannella J, et al. Research progress on mesenchymal stem cells (MSCs), adipose-derived mesenchymal stem cells (AD-MSCs), drugs, and vaccines in inhibiting COVID-19 disease. Aging Dis. 2020 Oct;11(5):1191–1201.
  • Gentile P. SARS-CoV-2: the “uncensored” truth about its origin and adipose-derived mesenchymal stem cells as new potential immune-modulatory weapon. Aging Dis. 2021 Apr;12(2):330–344.
  • Zhang Y, Ding J, Ren S, et al. Intravenous infusion of human umbilical cord Wharton’s jelly-derived mesenchymal stem cells as a potential treatment for patients with COVID-19 pneumonia. Stem Cell Res Ther. 2020 May 27 11(1):207.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.