Heterogeneity of mesenchymal stem cells: characterization and application in cell therapy

  • Xingzhi Liu School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, Anhui, China; and CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu, China
  • Zhihua Zhao CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu, China
  • Zhe Zhao CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu, China
  • Zhongjuan Xu School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei, Anhui, China; and CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu, China
  • Junjun Cao Livingchip Lnc., Nanjing, Jiangsu, China
  • Bin Wang Center for Clinic Stem Cell Research, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
  • Guangli Suo CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou, Jiangsu, China
Keywords: heterogeneity, mesenchymal stem cell, regenerative medicine, cell therapy

Abstract

Mesenchymal stem cells (MSCs) have shown great potentials in regenerative medicine for their low immunogenicity, multilineage differentiation potential, and extensive sources. However, the heterogeneity of MSCs limits their clinical application and industrial prospects. In this review, we introduced the heterogeneity of MSCs in terms of their applications, sources, functions, and surface markers; discussed the major factors leading to the heterogeneity in MSCs; summarized the main approaches to study the MSC heterogeneity, and addressed the clinical challenges resulting from heterogeneity. Finally, we proposed the strategies that might be used to purify the MSCs and to eliminate the heterogeneity of MSCs for their standardized production and reliable clinical application.

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References

Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: mesenchymal stem cells: their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells 2007; 25(11): 2739–49. doi: 10.1634/stemcells.2007-0197

Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4): 315–17. doi: 10.1080/14653240600855905

Alcayaga-Miranda F, Cuenca J, Khoury M. Antimicrobial activity of mesenchymal stem cells: current status and new perspectives of antimicrobial peptide-based therapies. Front Immunol. 2017; 8: 339. doi: 10.3389/fimmu.2017.00339

Cselenyák A, Pankotai E, Horváth EM, Kiss L, Lacza Z. Mesenchymal stem cells rescue cardiomyoblasts from cell death in an in vitro ischemia model via direct cell-to-cell connections. BMC Cell Biol 2010; 11: 29. doi: 10.1186/1471-2121-11-29

Zhang LB, He M. Effect of mesenchymal stromal (stem) cell (MSC) transplantation in asthmatic animal models: a systematic review and meta-analysis. Pulm Pharmacol Ther 2019; 54: 39–52. doi: 10.1016/j.pupt.2018.11.007

Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell 2011; 9(1): 11–15. doi: 10.1016/j.stem.2011.06.008

Li F, Han F, Li H, Zhang J, Qiao X, Shi J, et al. Human placental mesenchymal stem cells of fetal origins-alleviated inflammation and fibrosis by attenuating MyD88 signaling in bleomycin-induced pulmonary fibrosis mice. Mol Immunol. 2017; 90: 11–21. doi: 10.1016/j.molimm.2017.06.032

Ismail HD, Phedy P, Kholinne E, Djaja YP, Kusnadi Y, Merlina M, et al. Mesenchymal stem cell implantation in atrophic nonunion of the long bones: a translational study. Bone Joint Res 2016; 5(7): 287–293. doi: 10.1302/2046-3758.57.2000587

Suenaga H, Furukawa KS, Suzuki Y, Takato T, Ushida T. Bone regeneration in calvarial defects in a rat model by implantation of human bone marrow-derived mesenchymal stromal cell spheroids. J Mater Sci Mater Med 2015; 26(11): 254. doi: 10.1302/2046-3758.57.2000587

Zhang S, Chuah SJ, Lai RC, Hui JHP, Lim SK, Toh WS. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials 2018; 156: 16–27. doi: 10.1016/j.biomaterials.2017.11.028

Zhang K, Yan S, Li G, Cui L, Yin J. In-situ birth of MSCs multicellular spheroids in poly(L-glutamic acid)/chitosan scaffold for hyaline-like cartilage regeneration. Biomaterials 2015; 71: 24–34. doi: 10.1016/j.biomaterials.2015.08.037

Li J, Huang Y, Song J, Li X, Zhang X, Zhou Z, et al. Cartilage regeneration using arthroscopic flushing fluid-derived mesenchymal stem cells encapsulated in a one-step rapid cross-linked hydrogel. Acta Biomater 2018; 79: 202–15. doi: 10.1016/j.biomaterials.2015.08.037

Huang P, Wang L, Li Q, Xu J, Xu J, Xiong Y, et al. Combinatorial treatment of acute myocardial infarction using stem cells and their derived exosomes resulted in improved heart performance. Stem Cell Res Ther 2019; 10(1): 300. doi: 10.1186/s13287-019-1353-3

Park TY, Oh JM, Cho JS, Sim SB, Lee J, Cha HJ. Stem cell-loaded adhesive immiscible liquid for regeneration of myocardial infarction. J Control Release 2020; 321: 602–15. doi: 10.1186/s13287-019-1353-3

Zhou T, Li HY, Liao C, Lin W, Lin S. Clinical efficacy and safety of mesenchymal stem cells for systemic lupus erythematosus. Stem Cells Int 2020; 2020: 6518508. doi: 10.1155/2020/6518508

Zhao L, Chen S, Yang P, Cao H, Li L. The role of mesenchymal stem cells in hematopoietic stem cell transplantation: prevention and treatment of graft-versus-host disease. Stem Cell Res Ther 2019; 10(1): 182. doi: 10.1155/2020/6518508

Peng Z, Gao W, Yue B, Jiang J, Gu Y, Dai J, et al. Promotion of neurological recovery in rat spinal cord injury by mesenchymal stem cells loaded on nerve-guided collagen scaffold through increasing alternatively activated macrophage polarization. J Tissue Eng Regen Med 2018; 12(3): e1725–36. doi: 10.1155/2020/6518508

Wu GH, Shi HJ, Che MT, Huang MY, Wei QS, Feng B, et al. Recovery of paralyzed limb motor function in canine with complete spinal cord injury following implantation of MSC-derived neural network tissue. Biomaterials 2018; 181: 15–34. doi: 10.1016/j.biomaterials.2018.07.010

Almeida-Porada G, Porada CD, Tran N, Zanjani ED. Cotransplantation of human stromal cell progenitors into preimmune fetal sheep results in early appearance of human donor cells in circulation and boosts cell levels in bone marrow at later time points after transplantation. Blood 2000; 95(11): 3620–7. doi: 10.1182/blood.V95.11.3620

Noort WA, Kruisselbrink AB, in’t Anker PS, Kruger M, Van Bezooijen RL, De Paus RA, et al. Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34(+) cells in NOD/SCID mice. Exp Hematol 2002; 30(8): 870–8. doi: 10.1016/S0301-472X(02)00820-2

Koç ON, Gerson SL, Cooper BW, Dyhouse SM, Haynesworth SE, Caplan AI, et al. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol 2000; 18(2): 307–16. doi: 10.1200/JCO.2000.18.2.307

Shi R, Lian W, Jin Y, Cao C, Han S, Yang X, et al. Role and effect of vein-transplanted human umbilical cord mesenchymal stem cells in the repair of diabetic foot ulcers in rats. Acta Biochim Biophys Sin (Shanghai) 2020; 52(6): 620–30. doi: 10.1093/abbs/gmaa039

Petrou P, Kassis I, Levin N, Paul F, Backner Y, Benoliel T, et al. Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis. Brain 2020; 143(12): 3574–88. doi: 10.1093/brain/awaa333

Liang B, Chen J, Li T, Wu H, Yang W, Li Y, 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; 99(31): e21429. doi: 10.1097/MD.0000000000021429

Leng Z, Zhu R, Hou W, Feng Y, Yang Y, Han Q, et al. Transplantation of ACE2(-) mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia. Aging Dis 2020; 11(2): 216–28. doi: 10.1097/MD.0000000000021429

Atluri S, Manchikanti L, Hirsch JA. Expanded umbilical cord mesenchymal stem cells (UC-MSCs) as a therapeutic strategy in managing critically Ill COVID-19 patients: the case for compassionate use. Pain Physician. 2020; 23(2): E71–83. doi: 10.36076/ppj.2020/23/E71

Liu S, Peng D, Qiu H, Yang K, Fu Z, Zou L. Mesenchymal stem cells as a potential therapy for COVID-19. Stem Cell Res Ther 2020; 11(1): 169. doi: 10.1186/s13287-020-01678-8

Coelho A, Alvites RD, Branquinho MV, Guerreiro SG, Maurício AC. Mesenchymal stem cells (MSCs) as a potential therapeutic strategy in COVID-19 patients: literature research. Front Cell Dev Biol 2020; 8: 602647. doi: 10.3389/fcell.2020.602647

Rogers CJ, Harman RJ, Bunnell BA, Schreiber MA, Xiang C, Wang FS, et al. Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients. J Transl Med 2020; 18(1): 203. doi: 10.3389/fcell.2020.602647

Zumla A, Wang FS, Ippolito G, Petrosillo N, Agrati C, Azhar EI, et al. Reducing mortality and morbidity in patients with severe COVID-19 disease by advancing ongoing trials of Mesenchymal Stromal (stem) Cell (MSC) therapy – achieving global consensus and visibility for cellular host-directed therapies. Int J Infect Dis 2020; 96: 431–9. doi: 10.1016/j.ijid.2020.05.040

Kaffash Farkhad N, Reihani H, Sedaghat A, Moghadam AA, Moghadam AB, Tavakol-Afshari J. Are mesenchymal stem cells able to manage cytokine storm in COVID-19 patients? A review of recent studies. Regen Ther 2021; 18: 152–60. doi: 10.1016/j.ijid.2020.05.040

Shu L, Niu C, Li R, Huang T, Wang Y, Huang M, et al. Treatment of severe COVID-19 with human umbilical cord mesenchymal stem cells. Stem Cell Res Ther 2020; 11(1): 361. doi: 10.1016/j.ijid.2020.05.040

Shi L, Huang H, Lu X, Yan X, Jiang X, Xu R, et al. Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial. Signal Transduct Target Ther. 2021; 6(1): 58. doi: 10.1016/j.ijid.2020.05.040

Kouroupis D, Lanzoni G, Linetsky E, Messinger Cayetano S, Wishnek Metalonis S, Leñero C, et al. Umbilical cord-derived mesenchymal stem cells modulate TNF and soluble TNF receptor 2 (sTNFR2) in COVID-19 ARDS patients. Eur Rev Med Pharmacol Sci 2021; 25(12): 4435–8. doi: 10.26355/eurrev_202106_26156

Meng F, Xu R, Wang S, Xu Z, Zhang C, Li Y, et al. Human umbilical cord-derived mesenchymal stem cell therapy in patients with COVID-19: a phase 1 clinical trial. Signal Transduct Target Ther 2020; 5(1): 172. doi: 10.1016/j.ijid.2020.05.040

Chen X, Shan Y, Wen Y, Sun J, Du H. Mesenchymal stem cell therapy in severe COVID-19: a retrospective study of short-term treatment efficacy and side effects. J Infect 2020; 81(4): 647–79. doi: 10.1016/j.jinf.2020.05.020

Galipeau J, Sensébé L. Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell 2018; 22(6): 824–33. doi: 10.1016/j.stem.2018.05.004

Le Blanc K, Ringdén O. Immunomodulation by mesenchymal stem cells and clinical experience. J Intern Med 2007; 262(5): 509–25. doi: 10.1111/j.1365-2796.2007.01844.x

Levy O, Kuai R, Siren EMJ, Bhere D, Milton Y, Nissar N, et al. Shattering barriers toward clinically meaningful MSC therapies. Sci Adv 2020; 6(30): eaba6884. doi: 10.1126/sciadv.aba6884

Xie Y, Liu S, Wang L, Yang H, Tai C, Ling L, et al. Individual heterogeneity screened umbilical cord-derived mesenchymal stromal cells with high Treg promotion demonstrate improved recovery of mouse liver fibrosis. Stem Cell Res Ther 2021; 12(1): 359. doi: 10.1186/s13287-021-02430-6

Zhao Z, Wang Z, Li Q, Li W, You Y, Zou P. The different immunoregulatory functions of mesenchymal stem cells in patients with low-risk or high-risk myelodysplastic syndromes. PLoS One 2012; 7(9): e45675. doi: 10.1371/journal.pone.0045675

Phinney DG, Kopen G, Righter W, Webster S, Tremain N, Prockop DJ. Donor variation in the growth properties and osteogenic potential of human marrow stromal cells. J Cell Biochem 1999; 75(3): 424–36. doi: 10.1002/(SICI)1097-4644(19991201)75:3%3C424::AID-JCB8%3E3.0.CO;2-8

Phinney DG, Kopen G, Isaacson RL, Prockop DJ. Plastic adherent stromal cells from the bone marrow of commonly used strains of inbred mice: variations in yield, growth, and differentiation. J Cell Biochem 1999; 72(4): 570–85. doi: 10.1002/(SICI)1097-4644(19990315)72:4%3C570::AID-JCB12%3E3.0.CO;2-W

Zhou S, Greenberger JS, Epperly MW, Goff JP, Adler C, Leboff MS, et al. Age-related intrinsic changes in human bone-marrow-derived mesenchymal stem cells and their differentiation to osteoblasts. Aging Cell 2008; 7(3): 335–43. doi: 10.1111/j.1474-9726.2008.00377.x

Kang I, Lee BC, Choi SW, Lee JY, Kim JJ, Kim BE, et al. Donor-dependent variation of human umbilical cord blood mesenchymal stem cells in response to hypoxic preconditioning and amelioration of limb ischemia. Exp Mol Med 2018; 50(4): 1–15. doi: 10.1111/j.1474-9726.2008.00377.x

Cheng CC, Lee YH, Lin SP, Huangfu WC, Liu IH. Cell-autonomous heparanase modulates self-renewal and migration in bone marrow-derived mesenchymal stem cells. J Biomed Sci 2014; 21(1): 21. doi: 10.1186/1423-0127-21-21

Wagner W, Ho AD. Mesenchymal stem cell preparations – comparing apples and oranges. Stem Cell Rev 2007; 3(4): 239–48. doi: 10.1007/s12015-007-9001-1

Hung SP, Ho JH, Shih YR, Lo T, Lee OK. Hypoxia promotes proliferation and osteogenic differentiation potentials of human mesenchymal stem cells. J Orthop Res 2012; 30(2): 260–6. doi: 10.1002/jor.21517

Fotia C, Massa A, Boriani F, Baldini N, Granchi D. Hypoxia enhances proliferation and stemness of human adipose-derived mesenchymal stem cells. Cytotechnology 2015; 67(6): 1073–84. doi: 10.1007/s10616-014-9731-2

Holzwarth C, Vaegler M, Gieseke F, Pfister SM, Handgretinger R, Kerst G, et al. Low physiologic oxygen tensions reduce proliferation and differentiation of human multipotent mesenchymal stromal cells. BMC Cell Biol 2010; 11: 11. doi: 10.1186/1471-2121-11-11

Wang Y, Wu H, Yang Z, Chi Y, Meng L, Mao A, et al. Human mesenchymal stem cells possess different biological characteristics but do not change their therapeutic potential when cultured in serum free medium. Stem Cell Res Ther 2014; 5(6): 132. doi: 10.1186/scrt522

Ryan JM, Barry F, Murphy JM, Mahon BP. Interferon-gamma does not break, but promotes the immunosuppressive capacity of adult human mesenchymal stem cells. Clin Exp Immunol 2007; 149(2): 353–63. doi: 10.1111/j.1365-2249.2007.03422.x

Prasanna SJ, Gopalakrishnan D, Shankar SR, Vasandan AB. Pro-inflammatory cytokines, IFNgamma and TNFalpha, influence immune properties of human bone marrow and Wharton jelly mesenchymal stem cells differentially. PLoS One 2010; 5(2): e9016. doi: 10.1371/journal.pone.0009016

Cosgrove BD, Mui KL, Driscoll TP, Caliari SR, Mehta KD, Assoian RK, et al. N-cadherin adhesive interactions modulate matrix mechanosensing and fate commitment of mesenchymal stem cells. Nat Mater 2016; 15(12): 1297–306. doi: 10.1038/nmat4725

Cheng NC, Wang S, Young TH. The influence of spheroid formation of human adipose-derived stem cells on chitosan films on stemness and differentiation capabilities. Biomaterials 2012; 33(6): 1748–58. doi: 10.1016/j.biomaterials.2011.11.049

Araújo AB, Salton GD, Furlan JM, Schneider N, Angeli MH, Laureano Á M, et al. Comparison of human mesenchymal stromal cells from four neonatal tissues: amniotic membrane, chorionic membrane, placental decidua and umbilical cord. Cytotherapy 2017; 19(5): 577–85. doi: 10.1016/j.jcyt.2017.03.001

Stubbendorff M, Deuse T, Hua X, Phan TT, Bieback K, Atkinson K, et al. Immunological properties of extraembryonic human mesenchymal stromal cells derived from gestational tissue. Stem Cells Dev 2013; 22(19): 2619–29. doi: 10.1089/scd.2013.0043

Kern S, Eichler H, Stoeve J, Klüter H, Bieback K. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells 2006; 24(5): 1294–301. doi: 10.1634/stemcells.2005-0342

Hsiao ST, Asgari A, Lokmic Z, Sinclair R, Dusting GJ, Lim SY, et al. Comparative analysis of paracrine factor expression in human adult mesenchymal stem cells derived from bone marrow, adipose, and dermal tissue. Stem Cells Dev 2012; 21(12): 2189–203. doi: 10.1089/scd.2011.0674

Han ZC, Du WJ, Han ZB, Liang L. New insights into the heterogeneity and functional diversity of human mesenchymal stem cells. Biomed Mater Eng 2017; 28(Suppl 1): S29–45. doi: 10.3233/BME-171622

Lu LL, Liu YJ, Yang SG, Zhao QJ, Wang X, Gong W, et al. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica 2006; 91(8): 1017–26. doi: 10.3324/%25

Baksh D, Yao R, Tuan RS. Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells 2007; 25(6): 1384–92. doi: 10.1634/stemcells.2006-0709

Liu M, Yang SG, Shi L, Du WT, Liu PX, Xu J, et al. Mesenchymal stem cells from bone marrow show a stronger stimulating effect on megakaryocyte progenitor expansion than those from non-hematopoietic tissues. Platelets 2010; 21(3): 199–210. doi: 10.3109/09537101003602483

Salehinejad P, Alitheen NB, Ali AM, Omar AR, Mohit M, Janzamin E, et al. Comparison of different methods for the isolation of mesenchymal stem cells from human umbilical cord Wharton’s jelly. In Vitro Cell Dev Biol Anim 2012; 48(2): 75–83. doi: 10.1007/s11626-011-9480-x

Hua J, Gong J, Meng H, Xu B, Yao L, Qian M, et al. Comparison of different methods for the isolation of mesenchymal stem cells from umbilical cord matrix: proliferation and multilineage differentiation as compared to mesenchymal stem cells from umbilical cord blood and bone marrow. Cell Biol Int 2014; 38(2): 198–210. doi: 10.1002/cbin.10188

Horn P, Bork S, Diehlmann A, Walenda T, Eckstein V, Ho AD, et al. Isolation of human mesenchymal stromal cells is more efficient by red blood cell lysis. Cytotherapy 2008; 10(7): 676–85. doi: 10.1002/cbin.10188

Horn P, Bokermann G, Cholewa D, Bork S, Walenda T, Koch C, et al. Impact of individual platelet lysates on isolation and growth of human mesenchymal stromal cells. Cytotherapy 2010; 12(7): 888–98. doi: 10.3109/14653249.2010.501788

Hermida-Gómez T, Fuentes-Boquete I, Gimeno-Longas MJ, Muiños-López E, Díaz-Prado S, de Toro FJ, et al. Bone marrow cells immunomagnetically selected for CD271+ antigen promote in vitro the repair of articular cartilage defects. Tissue Eng Part A 2011; 17(7–8): 1169–79. doi: 10.1089/ten.tea.2010.0346

Yang ZX, Han ZB, Ji YR, Wang YW, Liang L, Chi Y, et al. CD106 identifies a subpopulation of mesenchymal stem cells with unique immunomodulatory properties. PLoS One 2013; 8(3): e59354. doi: 10.1089/ten.tea.2010.0346

Guérette D, Khan PA, Savard PE, Vincent M. Molecular evolution of type VI intermediate filament proteins. BMC Evol Biol 2007; 7: 164. doi: 10.1186/1471-2148-7-164

Yen BL, Huang HI, Chien CC, Jui HY, Ko BS, Yao M, et al. Isolation of multipotent cells from human term placenta. Stem Cells 2005; 23(1): 3–9. doi: 10.1634/stemcells.2004-0098

Wang W, Han ZC. Heterogeneity of human mesenchymal stromal/stem cells. Adv Exp Med Biol 2019; 1123: 165–77. doi: 10.1007/978-3-030-11096-3_10

Lv FJ, Tuan RS, Cheung KM, Leung VY. Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells 2014; 32(6): 1408–19. doi: 10.1007/978-3-030-11096-3_10

Bensidhoum M, Chapel A, Francois S, Demarquay C, Mazurier C, Fouillard L, et al. Homing of in vitro expanded Stro-1- or Stro-1+ human mesenchymal stem cells into the NOD/SCID mouse and their role in supporting human CD34 cell engraftment. Blood 2004; 103(9): 3313–19. doi: 10.1182/blood-2003-04-1121

Kuçi S, Kuçi Z, Kreyenberg H, Deak E, Pütsch K, Huenecke S, et al. CD271 antigen defines a subset of multipotent stromal cells with immunosuppressive and lymphohematopoietic engraftment-promoting properties. Haematologica 2010; 95(4): 651–9. doi: 10.3324/haematol.2009.015065

Sorrentino A, Ferracin M, Castelli G, Biffoni M, Tomaselli G, Baiocchi M, et al. Isolation and characterization of CD146+ multipotent mesenchymal stromal cells. Exp Hematol 2008; 36(8): 1035–46. doi: 10.3324/haematol.2009.015065

Mabuchi Y, Morikawa S, Harada S, Niibe K, Suzuki S, Renault-Mihara F, et al. LNGFR(+)THY-1(+)VCAM-1(hi+) cells reveal functionally distinct subpopulations in mesenchymal stem cells. Stem Cell Rep 2013; 1(2): 152–65. doi: 10.1016/j.stemcr.2013.06.001

Fukiage K, Aoyama T, Shibata KR, Otsuka S, Furu M, Kohno Y, et al. Expression of vascular cell adhesion molecule-1 indicates the differentiation potential of human bone marrow stromal cells. Biochem Biophys Res Commun 2008; 365(3): 406–12. doi: 10.1016/j.bbrc.2007.10.149

Gang EJ, Bosnakovski D, Figueiredo CA, Visser JW, Perlingeiro RC. SSEA-4 identifies mesenchymal stem cells from bone marrow. Blood 2007; 109(4): 1743–51. doi: 10.1182/blood-2005-11-010504

Zeddou M, Briquet A, Relic B, Josse C, Malaise MG, Gothot A, et al. The umbilical cord matrix is a better source of mesenchymal stem cells (MSC) than the umbilical cord blood. Cell Biol Int 2010; 34(7): 693–701. doi: 10.1042/CBI20090414

Wagner W, Wein F, Seckinger A, Frankhauser M, Wirkner U, Krause U, et al. Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp Hematol 2005; 33(11): 1402–16. doi: 10.1042/CBI20090414

Costa LA, Eiro N, Fraile M, Gonzalez LO, Saá J, Garcia-Portabella P, et al. Functional heterogeneity of mesenchymal stem cells from natural niches to culture conditions: implications for further clinical uses. Cell Mol Life Sci 2021; 78(2): 447–67. doi: 10.1007/s00018-020-03600-0

Kebriaei P, Hayes J, Daly A, Uberti J, Marks DI, Soiffer R, et al. A phase 3 randomized study of remestemcel-L versus placebo added to second-line therapy in patients with steroid-refractory acute graft-versus-host disease. Biol Blood Marrow Transplant 2020; 26(5): 835–44. doi: 10.1016/j.bbmt.2019.08.029

Kuçi Z, Bönig H, Kreyenberg H, Bunos M, Jauch A, Janssen JW, et al. Mesenchymal stromal cells from pooled mononuclear cells of multiple bone marrow donors as rescue therapy in pediatric severe steroid-refractory graft-versus-host disease: a multicenter survey. Haematologica 2016; 101(8): 985–94. doi: 10.3324/haematol.2015.140368

Sun C, Wang L, Wang H, Huang T, Yao W, Li J, et al. Single-cell RNA-seq highlights heterogeneity in human primary Wharton’s jelly mesenchymal stem/stromal cells cultured in vitro. Stem Cell Res Ther 2020; 11(1): 149. doi: 10.3324/haematol.2015.140368

Hou W, Duan L, Huang C, Li X, Xu X, Qin P, et al. Mesenchymal stem cell subpopulations and their heterogeneity of response to inductions revealed by single-cell RNA-seq. bioRxiv 2021:2021.05.07.443197. doi: 10.1101/2021.05.07.443197

Huang Y, Li Q, Zhang K, Hu M, Wang Y, Du L, et al. Single cell transcriptomic analysis of human mesenchymal stem cells reveals limited heterogeneity. Cell Death Dis 2019; 10(5): 368. doi: 10.1038/s41419-019-1583-4

Zhou W, Lin J, Zhao K, Jin K, He Q, Hu Y, et al. Single-cell profiles and clinically useful properties of human mesenchymal stem cells of adipose and bone marrow origin. Am J Sports Med 2019; 47(7): 1722–33. doi: 10.1177/0363546519848678

Wang Y, Dai W, Liu Z, Liu J, Cheng J, Li Y, et al. Single-cell infrared microspectroscopy quantifies dynamic heterogeneity of mesenchymal stem cells during adipogenic differentiation. Anal Chem 2021; 93(2): 671–6. doi: 10.1021/acs.analchem.0c04110

Russell KC, Phinney DG, Lacey MR, Barrilleaux BL, Meyertholen KE, O’Connor KC. In vitro high-capacity assay to quantify the clonal heterogeneity in trilineage potential of mesenchymal stem cells reveals a complex hierarchy of lineage commitment. Stem Cells 2010; 28(4): 788–98. doi: 10.1002/stem.312

Rennerfeldt DA, Raminhos JS, Leff SM, Manning P, Van Vliet KJ. Emergent heterogeneity in putative mesenchymal stem cell colonies: single-cell time lapsed analysis. PLoS One 2019; 14(4): e0213452. doi: 10.1371/journal.pone.0213452

Mareddy S, Broadbent J, Crawford R, Xiao Y. Proteomic profiling of distinct clonal populations of bone marrow mesenchymal stem cells. J Cell Biochem 2009; 106(5): 776–86. doi: 10.1002/jcb.22088

Moravcikova E, Meyer EM, Corselli M, Donnenberg VS, Donnenberg AD. Proteomic profiling of native unpassaged and culture-expanded mesenchymal stromal cells (MSC). Cytometry A 2018; 93(9): 894–904. doi: 10.1002/cyto.a.23574

Yin L, Wu Y, Yang Z, Tee CA, Denslin V, Lai Z, et al. Microfluidic label-free selection of mesenchymal stem cell subpopulation during culture expansion extends the chondrogenic potential in vitro. Lab Chip 2018; 18(6): 878–89. doi: 10.1039/C7LC01005B

Lam J, Marklein RA, Jimenez-Torres JA, Beebe DJ, Bauer SR, Sung KE. Adaptation of a simple microfluidic platform for high-dimensional quantitative morphological analysis of human mesenchymal stromal cells on polystyrene-based substrates. SLAS Technol 2017; 22(6): 646–61. doi: 10.1177/2472630317726050

Liu Z, Screven R, Yu D, Boxer L, Myers MJ, Han J, et al. Microfluidic separation of canine adipose-derived mesenchymal stromal cells. Tissue Eng Part C Methods 2021; 27(8): 445–61. doi: 10.1089/ten.tec.2021.0082

Bloor AJC, Patel A, Griffin JE, Gilleece MH, Radia R, Yeung DT, et al. Production, safety and efficacy of iPSC-derived mesenchymal stromal cells in acute steroid-resistant graft versus host disease: a phase I, multicenter, open-label, dose-escalation study. Nat Med 2020; 26(11): 1720–5. doi: 10.1038/s41591-020-1050-x

Ozay EI, Vijayaraghavan J, Gonzalez-Perez G, Shanthalingam S, Sherman HL, Garrigan DT, Jr., et al. Cymerus™ iPSC-MSCs significantly prolong survival in a pre-clinical, humanized mouse model of Graft-vs-host disease. Stem Cell Res 2019; 35: 101401. doi: 10.1016/j.scr.2019.101401

Hu X, Li L, Yu X, Zhang R, Yan S, Zeng Z, et al. CRISPR/Cas9-mediated reversibly immortalized mouse bone marrow stromal stem cells (BMSCs) retain multipotent features of mesenchymal stem cells (MSCs). Oncotarget 2017; 8(67): 111847–65. doi: 10.18632/oncotarget.22915

Sarker SR, Aoshima Y, Hokama R, Inoue T, Sou K, Takeoka S. Arginine-based cationic liposomes for efficient in vitro plasmid DNA delivery with low cytotoxicity. Int J Nanomed 2013; 8: 1361–75. doi: 10.2147/IJN.S38903

Zabaleta N, Barberia M, Martin-Higueras C, Zapata-Linares N, Betancor I, Rodriguez S, et al. CRISPR/Cas9-mediated glycolate oxidase disruption is an efficacious and safe treatment for primary hyperoxaluria type I. Nat Commun 2018; 9(1): 5454. doi: 10.1038/s41467-018-07827-1

Qiao Y, Xu Z, Yu Y, Hou S, Geng J, Xiao T, et al. Single cell derived spheres of umbilical cord mesenchymal stem cells enhance cell stemness properties, survival ability and therapeutic potential on liver failure. Biomaterials 2020; 227: 119573. doi: 10.1016/j.biomaterials.2019.119573

Published
2022-01-05
How to Cite
LiuX., ZhaoZ., ZhaoZ., XuZ., CaoJ., WangB., & SuoG. (2022). Heterogeneity of mesenchymal stem cells: characterization and application in cell therapy. STEMedicine, 3(1), e109. https://doi.org/10.37175/stemedicine.v3i1.109
Section
Review articles