Int J Stem Cells.  2016 Nov;9(2):163-168. 10.15283/ijsc16053.

Therapeutic Potential of Human Mesenchymal Stem Cells for Treating Ischemic Limb Diseases

• Han KH
• Kim AK
• Kim DI

• KMID: 2362509
• DOI: http://doi.org/10.15283/ijsc16053

Abstract

Ischemic limb diseases are induced by different obstructions of peripheral arteries. These obstructions result in insufficient nutrient and oxygen supplies to the extremities, thereby leading to severe tissue damage that is in turn related to severe morbidities and mortalities. Mesenchymal stem cells (MSCs) have been isolated from various sources. These cells are multipotent with respect to differentiation and are also characterized by migration, immune suppression, and secretion of paracrine factors. Mesenchymal stem cells have been proposed to have therapeutic potential for the treatment of ischemic limb diseases. In preclinical experiments, injection of single MSCs has been shown to increase angiogenesis and blood flow in ischemic hindlimb animal models; several molecular mechanisms of angiogenesis have also been elucidated. Furthermore, modified strategies have been developed for enhancing angiogenesis and the efficacy of MSCs. These strategies have demonstrated significant effects in pre-clinical studies. In clinical trials, MSCs have shown significant effects in the treatment of ischemic limb diseases. In this review, we focus on the therapeutic properties of human MSCs and the modified methods for enhancing angiogenesis in pre-clinical experiments. We also discuss the clinical applications of MSCs for treating limb ischemia.

Keyword

Angiogenesis; Ischemic limb disease; Human mesenchymal stem cell

MeSH Terms

Animals
Arteries
Equipment and Supplies
Extremities*
Hindlimb
Humans*
Ischemia
Mesenchymal Stromal Cells*
Models, Animal
Mortality
Oxygen
Oxygen

Reference

References

1. Herten M, Torsello GB, Schönefeld E, Stahlhoff S. Critical appraisal of paclitaxel balloon angioplasty for femoral-popliteal arterial disease. Vasc Health Risk Manag. 2016; 12:341–356. DOI: 10.2147/VHRM.S81122. PMID: 27621646. PMCID: 5010165.

2. Spees JL, Lee RH, Gregory CA. Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Res Ther. 2016; 7:125. DOI: 10.1186/s13287-016-0363-7. PMID: 27581859. PMCID: 5007684.

3. Cao Y, Sun Z, Liao L, Meng Y, Han Q, Zhao RC. Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. Biochem Biophys Res Commun. 2005; 332:370–379. DOI: 10.1016/j.bbrc.2005.04.135. PMID: 15896706.

4. Poitevin S, Cussac D, Leroyer AS, Albinet V, Sarlon-Bartoli G, Guillet B, Hubert L, Andrieu-Abadie N, Couderc B, Parini A, Dignat-George F, Sabatier F. Sphingosine kinase 1 expressed by endothelial colony-forming cells has a critical role in their revascularization activity. Cardiovasc Res. 2014; 103:121–130. DOI: 10.1093/cvr/cvu104. PMID: 24743591.

5. Han KH, Kim AK, Kim MH, Kim DH, Go HN, Kim DI. Enhancement of angiogenic effects by hypoxia-preconditioned human umbilical cord-derived mesenchymal stem cells in a mouse model of hindlimb ischemia. Cell Biol Int. 2016; 40:27–35. DOI: 10.1002/cbin.10519.

6. Huang CC, Pan WY, Tseng MT, Lin KJ, Yang YP, Tsai HW, Hwang SM, Chang Y, Wei HJ, Sung HW. Enhancement of cell adhesion, retention, and survival of HUVEC/cbMSC aggregates that are transplanted in ischemic tissues by concurrent delivery of an antioxidant for therapeutic angiogenesis. Biomaterials. 2016; 74:53–63. DOI: 10.1016/j.biomaterials.2015.09.043.

7. Ishii M, Shibata R, Numaguchi Y, Kito T, Suzuki H, Shimizu K, Ito A, Honda H, Murohara T. Enhanced angiogenesis by transplantation of mesenchymal stem cell sheet created by a novel magnetic tissue engineering method. Arterioscler Thromb Vasc Biol. 2011; 31:2210–2215. DOI: 10.1161/ATVBAHA.111.231100. PMID: 21757660.

8. Landázuri N, Levit RD, Joseph G, Ortega-Legaspi JM, Flores CA, Weiss D, Sambanis A, Weber CJ, Safley SA, Taylor WR. Alginate microencapsulation of human mesenchymal stem cells as a strategy to enhance paracrine-mediated vascular recovery after hindlimb ischaemia. J Tissue Eng Regen Med. 2016; 10:222–232. DOI: 10.1002/term.1680.

9. Lee JH, Han YS, Lee SH. Long-duration three-dimensional spheroid culture promotes angiogenic activities of adipose-derived mesenchymal stem cells. Biomol Ther (Seoul). 2016; 24:260–267. DOI: 10.4062/biomolther.2015.146.

10. Park WS, Heo SC, Jeon ES, Hong da H, Son YK, Ko JH, Kim HK, Lee SY, Kim JH, Han J. Functional expression of smooth muscle-specific ion channels in TGF-β(1)-treated human adipose-derived mesenchymal stem cells. Am J Physiol Cell Physiol. 2013; 305:C377–C391. DOI: 10.1152/ajpcell.00404.2012. PMID: 23761629. PMCID: 3891216.

11. Yin T, He S, Su C, Chen X, Zhang D, Wan Y, Ye T, Shen G, Wang Y, Shi H, Yang L, Wei Y. Genetically modified human placenta–derived mesenchymal stem cells with FGF–2 and PDGF–BB enhance neovascularization in a model of hindlimb ischemia. Mol Med Rep. 2015; 12:5093–5099. PMID: 26239842. PMCID: 4581748.

12. Zhang HC, Liu XB, Huang S, Bi XY, Wang HX, Xie LX, Wang YQ, Cao XF, Lv J, Xiao FJ, Yang Y, Guo ZK. Microvesicles derived from human umbilical cord mesenchymal stem cells stimulated by hypoxia promote angiogenesis both in vitro and in vivo. Stem Cells Dev. 2012; 21:3289–3297. DOI: 10.1089/scd.2012.0095. PMID: 22839741. PMCID: 3516422.

13. Powell RJ, Marston WA, Berceli SA, Guzman R, Henry TD, Longcore AT, Stern TP, Watling S, Bartel RL. Cellular therapy with Ixmyelocel-T to treat critical limb ischemia: the randomized, double-blind, placebo-controlled RESTORE-CLI trial. Mol Ther. 2012; 20:1280–1286. DOI: 10.1038/mt.2012.52. PMID: 22453769. PMCID: 3369291.

14. Hass R, Kasper C, Böhm S, Jacobs R. Different populations and sources of human mesenchymal stem cells (MSC): a comparison of adult and neonatal tissue-derived MSC. Cell Commun Signal. 2011; 9:12. DOI: 10.1186/1478-811X-9-12. PMID: 21569606. PMCID: 3117820.

15. Kolf CM, Cho E, Tuan RS. Mesenchymal stromal cells. Biology of adult mesenchymal stem cells: regulation of niche, self-renewal and differentiation. Arthritis Res Ther. 2007; 9:204. DOI: 10.1186/ar2116. PMID: 17316462. PMCID: 1860068.

16. Cook D, Genever P. Regulation of mesenchymal stem cell differentiation. Adv Exp Med Biol. 2013; 786:213–229. DOI: 10.1007/978-94-007-6621-1_12. PMID: 23696359.

17. Zhang SJ, Song XY, He M, Yu SB. Effect of TGF-β 1/SDF-1/CXCR4 signal on BM-MSCs homing in rat heart of ischemia/perfusion injury. Eur Rev Med Pharmacol Sci. 2016; 20:899–905. PMID: 27010148.

18. Xie C, Jin J, Lv X, Tao J, Wang R, Miao D. Anti-aging effect of transplanted amniotic membrane mesenchymal stem cells in a premature aging model of Bmi-1 deficiency. Sci Rep. 2015; 5:13975. DOI: 10.1038/srep13975. PMID: 26370922. PMCID: 4570627.

19. Gao F, Chiu SM, Motan DA, Zhang Z, Chen L, Ji HL, Tse HF, Fu QL, Lian Q. Mesenchymal stem cells and immunomodulation: current status and future prospects. Cell Death Dis. 2016; 7:e2062. DOI: 10.1038/cddis.2015.327. PMID: 26794657. PMCID: 4816164.

20. Gnecchi M, Zhang Z, Ni A, Dzau VJ. Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008; 103:1204–1219. DOI: 10.1161/CIRCRESAHA.108.176826. PMID: 19028920. PMCID: 2667788.

21. Park HW, Chang JW, Yang YS, Oh W, Hwang JH, Kim DG, Paek SH. The effect of donor-dependent administration of human umbilical cord blood-derived mesenchymal stem cells following focal cerebral ischemia in rats. Exp Neurobiol. 2015; 24:358–365. DOI: 10.5607/en.2015.24.4.358. PMID: 26713083. PMCID: 4688335.

22. Kim Y, Kim H, Cho H, Bae Y, Suh K, Jung J. Direct comparison of human mesenchymal stem cells derived from adipose tissues and bone marrow in mediating neovascularization in response to vascular ischemia. Cell Physiol Biochem. 2007; 20:867–876. DOI: 10.1159/000110447. PMID: 17982269.

23. Yamahara K, Harada K, Ohshima M, Ishikane S, Ohnishi S, Tsuda H, Otani K, Taguchi A, Soma T, Ogawa H, Katsuragi S, Yoshimatsu J, Harada-Shiba M, Kangawa K, Ikeda T. Comparison of angiogenic, cytoprotective, and immunosuppressive properties of human amnion- and chorion-derived mesenchymal stem cells. PLoS One. 2014; 9:e88319. DOI: 10.1371/journal.pone.0088319. PMID: 24551087. PMCID: 3925106.

24. Czapla J, Matuszczak S, Wiśniewska E, Jarosz-Biej M, Smolarczyk R, Cichoń T, Głowala-Kosińska M, Śliwka J, Garbacz M, Szczypior M, Jaźwiec T, Langrzyk A, Zembala M, Szala S. Human cardiac mesenchymal stromal cells with CD105+CD34− phenotype enhance the function of post-infarction heart in mice. PLoS One. 2016; 11:e0158745. DOI: 10.1371/journal.pone.0158745.

25. Du W, Li X, Chi Y, Ma F, Li Z, Yang S, Song B, Cui J, Ma T, Li J, Tian J, Yang Z, Feng X, Chen F, Lu S, Liang L, Han ZB, Han ZC. VCAM-1+ placenta chorionic villi-derived mesenchymal stem cells display potent pro-angiogenic activity. Stem Cell Res Ther. 2016; 7:49. DOI: 10.1186/s13287-016-0297-0. PMID: 27044487. PMCID: 4820943.

26. Laurila JP, Laatikainen L, Castellone MD, Trivedi P, Heikkila J, Hinkkanen A, Hematti P, Laukkanen MO. Human embryonic stem cell-derived mesenchymal stromal cell transplantation in a rat hind limb injury model. Cytotherapy. 2009; 11:726–737. DOI: 10.3109/14653240903067299. PMID: 19878059. PMCID: 2889035.

27. Lian Q, Zhang Y, Zhang J, Zhang HK, Wu X, Zhang Y, Lam FF, Kang S, Xia JC, Lai WH, Au KW, Chow YY, Siu CW, Lee CN, Tse HF. Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemia in mice. Circulation. 2010; 121:1113–1123. DOI: 10.1161/CIRCULATIONAHA.109.898312. PMID: 20176987.

28. Camussi G, Deregibus MC, Bruno S, Cantaluppi V, Biancone L. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int. 2010; 78:838–848. DOI: 10.1038/ki.2010.278. PMID: 20703216.

29. 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; 33:1748–1758. DOI: 10.1016/j.biomaterials.2011.11.049.

30. Yeh HY, Liu BH, Sieber M, Hsu SH. Substrate-dependent gene regulation of self-assembled human MSC spheroids on chitosan membranes. BMC Genomics. 2014; 15:10. DOI: 10.1186/1471-2164-15-10. PMID: 24387160. PMCID: 4046657.

31. Yoon HH, Bhang SH, Shin JY, Shin J, Kim BS. Enhanced cartilage formation via three-dimensional cell engineering of human adipose-derived stem cells. Tissue Eng Part A. 2012; 18:1949–1956. DOI: 10.1089/ten.tea.2011.0647. PMID: 22881427. PMCID: 3463274.

32. Chang HK, Kim PH, Cho HM, Yum SY, Choi YJ, Son Y, Lee D, Kang I, Kang KS, Jang G, Cho JY. Inducible HGF-secreting human umbilical cord blood-derived MSCs produced via TALEN-mediated genome editing promoted angiogenesis. Mol Ther. 2016; 24:1644–1654. DOI: 10.1038/mt.2016.120. PMID: 27434585.

33. Guiducci S, Porta F, Saccardi R, Guidi S, Ibba-Manneschi L, Manetti M, Mazzanti B, Dal Pozzo S, Milia AF, Bellando-Randone S, Miniati I, Fiori G, Fontana R, Amanzi L, Braschi F, Bosi A, Matucci-Cerinic M. Autologous mesenchymal stem cells foster revascularization of ischemic limbs in systemic sclerosis: a case report. Ann Intern Med. 2010; 153:650–654. DOI: 10.7326/0003-4819-153-10-201011160-00007. PMID: 21079220.

34. Gupta PK, Chullikana A, Parakh R, Desai S, Das A, Gottipamula S, Krishnamurthy S, Anthony N, Pherwani A, Majumdar AS. A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia. J Transl Med. 2013; 11:143. DOI: 10.1186/1479-5876-11-143. PMID: 23758736. PMCID: 3688296.

35. Bura A, Planat-Benard V, Bourin P, Silvestre JS, Gross F, Grolleau JL, Saint-Lebese B, Peyrafitte JA, Fleury S, Gadelorge M, Taurand M, Dupuis-Coronas S, Leobon B, Casteilla L. Phase I trial: the use of autologous cultured adipose-derived stroma/stem cells to treat patients with non-revascularizable critical limb ischemia. Cytotherapy. 2014; 16:245–257. DOI: 10.1016/j.jcyt.2013.11.011. PMID: 24438903.

36. Lee HC, An SG, Lee HW, Park JS, Cha KS, Hong TJ, Park JH, Lee SY, Kim SP, Kim YD, Chung SW, Bae YC, Shin YB, Kim JI, Jung JS. Safety and effect of adipose tissue-derived stem cell implantation in patients with critical limb ischemia: a pilot study. Circ J. 2012; 76:1750–1760. DOI: 10.1253/circj.CJ-11-1135. PMID: 22498564.

37. Brewster L, Robinson S, Wang R, Griffiths S, Li H, Peister A, Copland I, McDevitt T. Expansion and angiogenic potential of mesenchymal stem cells from patients with critical limb ischemia. J Vasc Surg. 2016; DOI: 10.1016/j.jvs.2015.02.061.

38. Smadja DM, d’Audigier C, Guerin CL, Mauge L, Dizier B, Silvestre JS, Dal Cortivo L, Gaussem P, Emmerich J. Angiogenic potential of BM MSCs derived from patients with critical leg ischemia. Bone Marrow Transplant. 2012; 47:997–1000. DOI: 10.1038/bmt.2011.196.