Skip to main content
PMC home page
The Indian Journal of Surgery logoLink to The Indian Journal of Surgery
. 2009 Sep 2;71(4):177–181. doi: 10.1007/s12262-009-0059-7

Stem cell therapy for critical limb ischaemia — a review

Anjan Kumar Das 1,✉
PMCID: PMC3452627  PMID: 23133150

Abstract

Critical limb ischaemia is an intractable condition associated with high levels of amputation, leading to a low quality of life and increased morbidity and mortality. It is often not treatable by standard therapeutic modalities. Neoangiogenesis has been proposed as a novel method of treatment of such patients. Vascular endothelial growth factor (VEGF) and cytokine fibroblast growth factor (FGF-1) have been shown to elicit neoangiogenesis. Stem cells are progenitor cells which can differentiate in vivo into different types of cells. Mesenchymal stem cells (MSCs) are a type of adult stem cells which have an immunomodulatory effect. Stem cell therapy has been used in animal studies to improve limb vascularity in rat and rabbit models. Several clinical studies have also validated their use for critical limb ischaemia. However many issues are still unresolved. These include the dosage, delivery and safety issues in relation to stem cell therapy. However stem cells are likely to be an important therapeutic modality to treat critical limb ischaemia in the near future.

Keywords: Stem cells, Critical limb ischaemia, Neoangiogenesis

Full Text

The Full Text of this article is available as a PDF (492.7 KB).

References

  • 1.Norgren L., Hiatt W.R., Dormandy J.A., Nehler M.R., Harris K.A., Fowkes F.G. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) Eur J Vasc Endovasc Surg. 2007;33:S1–S75. doi: 10.1016/j.ejvs.2006.09.024. [DOI] [PubMed] [Google Scholar]
  • 2.Hirsch A.T., Criqui M.H., Treat-Jacobson D., et al. Peripheral arterial disease detection, awareness, and treatment in primary care. JAMA. 2001;286:1317–1324. doi: 10.1001/jama.286.11.1317. [DOI] [PubMed] [Google Scholar]
  • 3.Anon (1996) Critical Limb Ischaemia: management and outcome: Report of a National Survey: The Vascular Society of Great Britain and Ireland. Eur J Endovac Surg 12: 131–135 [DOI] [PubMed]
  • 4.Anon (2005) Lower extremity disease among persons aged > or=40 years with and without diabetes—United States, 1999–2002. Centers for Disease Control and Prevention (CDC). MMWR Morb Mortal Wkly Rep 54: 1158–1160 [PubMed]
  • 5.Dormandy J.A., Rutherford R.B. Management of peripheral arterial disease (PAD). TASC Working Group. TransAtlantic Inter-Society Consensus (TASC) J Vasc Surg. 2000;31:S1–S296. doi: 10.1016/S0741-5214(00)70062-0. [DOI] [PubMed] [Google Scholar]
  • 6.Albers M., Fratezi A.C., De L.N. Assessment of quality of life of patients with severe ischaemia as a result of infrainguinal arterial occlusive disease. J Vasc Surg. 1992;6:54–59. [PubMed] [Google Scholar]
  • 7.Dormandy J., Heeck L., Vig S. Predicting which patients will develop chronic critical leg ischaemia. Semin Vasc Surg. 1999;12:138–141. [PubMed] [Google Scholar]
  • 8.Schainfeld R.M., Isner J.M. Critical limb ischaemia: nothing to give at the office? Ann Intern Med. 1999;130:442–444. doi: 10.7326/0003-4819-130-5-199903020-00017. [DOI] [PubMed] [Google Scholar]
  • 9.Milkiewicz M., Pugh C.W., Egginton S. Inhibition of endogenous HIF inactivation induces angiogenesis in ischaemic skeletal muscles of mice. J Physiol. 2004;560:21–26. doi: 10.1113/jphysiol.2004.069757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Oakley R.M., Seow K.K., Tang T.P., Kok C.W., Teh M., Lim Y.T., Lim S.K. Whole bone marrow transplantation induces angiogenesis following acute ischaemia. Redox Rep. 2002;7:215–218. doi: 10.1179/135100002125000532. [DOI] [PubMed] [Google Scholar]
  • 11.Asahara T., Murohara T., Sullivan A., et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964–967. doi: 10.1126/science.275.5302.964. [DOI] [PubMed] [Google Scholar]
  • 12.Ippokratis P., Giannoudis P. V. Biology of mesenchymal stem cells injury. Int J Care Injured. 2005;36S:S8–S12. doi: 10.1016/j.injury.2005.07.028. [DOI] [PubMed] [Google Scholar]
  • 13.Gerwins P., Skoldenberg E., Claesson-Welsh L. Function of fibroblast growth factors and vascular endothelial growth factors and their receptors in angiogenesis. Crit Rev Oncol Hematol. 2000;34:185–194. doi: 10.1016/S1040-8428(00)00062-7. [DOI] [PubMed] [Google Scholar]
  • 14.Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–1186. doi: 10.1056/NEJM197111182852108. [DOI] [PubMed] [Google Scholar]
  • 15.Pu L.Q., Sniderman A.D., Brassard R., Lachapelle K.J., Graham A.M., Lisbona R., Symes J.F. Enhanced revascularization of the ischemic limb by angiogenic therapy. Circulation. 1993;88:208–215. doi: 10.1161/01.cir.88.1.208. [DOI] [PubMed] [Google Scholar]
  • 16.Weel V., Deckers M.M., Grimbergen J.M., Leuven K.J., Lardenoye J.H., Schlingemann R.O., Nieuw Amerongen G.P., Bockel J.H., Hinsbergh V.W., Quax P.H. Vascular endothelial growth factor overexpression in ischemic skeletal muscle enhances myoglobin expression in vivo. Circ Res. 2004;95:58–66. doi: 10.1161/01.RES.0000133247.69803.c3. [DOI] [PubMed] [Google Scholar]
  • 17.McDonnell K., Bowden E.T., Cabal-Manzano R., Hoxter B., Riegel A.T., Wellstein A. Vascular leakage in chick embryos after expression of a secreted binding protein for fibroblast growth factors. Lab Invest. 2005;85:747–755. doi: 10.1038/labinvest.3700269. [DOI] [PubMed] [Google Scholar]
  • 18.Hirata K., Li T.-S., Nishida M., Ito H., Matsuzaki M., Kasaoka S., Harmano K. Autologous bone marrow cell implantation as therapeutic angiogenesis for ischemic hindlimb in diabetic rat model. Am J Heart Care Physiol. 2003;284:66–70. doi: 10.1152/ajpheart.00547.2002. [DOI] [PubMed] [Google Scholar]
  • 19.Tateishi-Yuyama E., Matsubara H., Murohara T., Ikeda U., Shintani S., Masaki H., Amano K., Kishimoto Y., Yoshimoto K., Akashi H. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bonemarrow cells: a pilot study and a randomised controlled trial. Lancet. 2002;360:427–435. doi: 10.1016/S0140-6736(02)09670-8. [DOI] [PubMed] [Google Scholar]
  • 20.Sprengers R.W., Lips D.L., Moll F.L., Verhaar M.C. Progenitor cell therapy in patients with critical limb ischaemia without surgical options. Ann Surg. 2008;247:411–420. doi: 10.1097/SLA.0b013e318153fdcb. [DOI] [PubMed] [Google Scholar]
  • 21.Shibata T., Naruse K., Kamiya H., Kozakae M., Kondo M., Yasuda Y., Nakamura N., Ota K., Tosaki T., Matsuki T., et al. Transplantation of bone marrow-derived mesenchymal stem cells improves diabetic polyneuropathy in rats diabetes. 2008;57(11):3099–3107. doi: 10.2337/db08-0031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Waters R.E., Terjung R.L., Peters K.G., Annex B.H. Preclinical models of human peripheral arterial occlusive disease: implications for investigation of therapeutic agents. J Appl Physiol. 2004;97(2):773–780. doi: 10.1152/japplphysiol.00107.2004. [DOI] [PubMed] [Google Scholar]
  • 23.Hori Y., Gu X., Xie X., Kim S.K. Differentiation of insulin-producing cells from human neural progenitor cells. PLoS Med. 2005;2:e103. doi: 10.1371/journal.pmed.0020103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Kajiguchi M., Kondo T., Izawa H., Kobayashi M., Yamamoto K., Shintani S., Numaguchi Y., Naoe T., Takamatsu J., Komori K., Murohara T. Safety and efficacy of autologous progenitor cell transplantation for therapeutic angiogenesis in patients with critical limb ischaemia. Circ J. 2007;71:196–201. doi: 10.1253/circj.71.196. [DOI] [PubMed] [Google Scholar]
  • 25.Lenk K., Adams V., Lurz P., Erbs S., Linke A., Gielen S., Schmidt A., Scheinert D., Biamino G., Emmrich F., Schuler G., Hambrecht R. Therapeutical potential of bloodderived progenitor cells in patients with peripheral arterial occlusive disease and critical limb ischaemia. Eur Heart J. 2005;26:1903–1909. doi: 10.1093/eurheartj/ehi285. [DOI] [PubMed] [Google Scholar]
  • 26.Bartsch T., Brehm M., Zeus T., et al. Autologous mononuclear stem cell transplantation in patients with peripheral occlusive arterial disease. Cardiovasc Nurs. 2006;21:430–432. doi: 10.1097/00005082-200611000-00003. [DOI] [PubMed] [Google Scholar]
  • 27.Bartsch T., Brehm M., Zeus T., Kögler G., Wernet P., Strauer B.E. Transplantation of autologous mononuclear bone marrow stem cells in patients with peripheral arterial disease (The TAM-PAD study) Clin Res Cardiol. 2007;96(12):891–899. doi: 10.1007/s00392-007-0569-x. [DOI] [PubMed] [Google Scholar]
  • 28.Kim D.-I., Kim M.-J., Joh J.-H., Shin S.-W., Do Y.-S., Moon J.Y., Kim N.-R., Lim J.-E., Kim A.-K., Eo H.-S., Kim B.-S., Cho S.-W., Yang S.-H., Park C.-J., Shim J.-S. Angiogenesis facilitated by autologous whole bone marrow stem cell transplantation for Buerger’s disease. Stem Cells. 2006;24:1194–1200. doi: 10.1634/stemcells.2005-0349. [DOI] [PubMed] [Google Scholar]

Articles from The Indian Journal of Surgery are provided here courtesy of Springer

RESOURCES