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Autologous transplantation of CD34+ bone marrow derived mononuclear cells in management of non-reconstructable critical lower limb ischemia

Cytotechnology volume 68, pages 771–781 (2016)Cite this article

Abstract

Patients with a decrease in limb perfusion with a potential threat to limb viability manifested by ischemic rest pain, ischemic ulcers, and/or gangrene are considered to have critical limb ischemia (CLI). Because of this generally poor outcome, there is a strong need for attempting any procedure to save the affected limb. The aim of this work is to evaluate the possibility to use stem cell therapy as a treatment option for patients with chronic critical lower limb ischemia with no distal run off. This study includes 20 patients with chronic critical lower limb ischemia with no distal run off who are unsuitable for vascular or endovascular option. These patients underwent stem cell therapy (SCT) by autologous transplantation of bone marrow derived mononuclear cells. 55 % of patients treated with SCT showed improvement of the rest pain after the first month, 60 % continued improvement of the rest pain after 6 months, 75 % after 1 year and 80 % after 2 years and continued without any deterioration till the third year. Limb salvage rate after STC was 80 % after the first year till the end of the second and third years. SCT can result in angiogenesis in patients with no-option CLI, providing a foundation for the application of this therapy to leg ischemia.

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References

  • Asahara T, Takahashi T, Masuda H, Kalka C, Chen D, Iwaguro H, Isner M (1999) VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 18:3964–3972

    CAS  Article  Google Scholar 

  • Attanasio S, Snell J (2009) Therapeutic angiogenesis in the management of critical limb ischemia: current concepts and review. Cardiol Rev 17:115–120

    Article  Google Scholar 

  • Botti C, Maione C, Coppola A, Sica V, Cobellis G (2012) Autologous bone marrow cell therapy for peripheral arterial disease. Stem Cells Cloning 5:5–14

    CAS  Google Scholar 

  • Burt K, Loh Y, Pearce W, Beohar N, Barr G, Craig R, Kessler J (2008) Clinical applications of blood-derived and marrow-derived stem cells for nonmalignant diseases. JAMA 299:925–936

    CAS  Article  Google Scholar 

  • Bussolino F, Ziche M, Wang M, Alessi D, Morbidelli L, Cremona O, Mantovani A (1991) In vitro and in vivo activation of endothelial cells by colony-stimulating factors. J Clin Invest 87:986–995

    CAS  Article  Google Scholar 

  • Casamassimi A, Grimaldi V, Infante T, Al-Omran M, Crudele V, Napoli C (2012) Adult stem cells and the clinical arena: are we able to widely use this therapy in patients with chronic limbs arteriopathy and ischemic ulcers without possibility of revascularization? Cardiovasc Hematol Agents Med Chem 10:99–108

    CAS  Article  Google Scholar 

  • Chochola M, Pytlik R, Kobylka P, Skalicka L, Kideryova L, Beran S, Linhart A (2008) Autologous intra-arterial infusion of bone marrow mononuclear cells in patients with critical leg ischemia. Int Angiol 27:281–290

    CAS  Google Scholar 

  • Corona T, Rathbone R (2014) Accelerated functional recovery after skeletal muscle ischemia-reperfusion injury using freshly isolated bone marrow cells. J Surg Res 188:100–109

    CAS  Article  Google Scholar 

  • Dormandy J, Heeck L, Vig S (1999) Major amputations: clinical patterns and predictors. [Review]. Semin Vasc Surg 12:154–161

    CAS  Google Scholar 

  • Duong Van Huyen P, Smadja M, Bruneval P, Gaussem P, Dal-Cortivo L, Julia P, Emmerich J (2008) Bone marrow-derived mononuclear cell therapy induces distal angiogenesis after local injection in critical leg ischemia. Mod Pathol 21:837–846

    Article  Google Scholar 

  • Fischer M, Harting T, Jimenez F, Monzon-Posadas O, Xue H, Savitz I, Cox S (2009) Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev 18:683–692

    CAS  Article  Google Scholar 

  • Gao J, Dennis E, Muzic F, Lundberg M, Caplan I (2001) The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 169:12–20

    CAS  Article  Google Scholar 

  • Guiducci S, Porta F, Saccardi R, Guidi S, Ibba-Manneschi L, Manetti M, Matucci-Cerinic M (2010) Autologous mesenchymal stem cells foster revascularization of ischemic limbs in systemic sclerosis: a case report. Ann Intern Med 153:650–654

    Article  Google Scholar 

  • Hirsch T, Haskal J, Hertzer R, Bakal W, Creager A, Halperin L, Vascular Disease F (2006) ACC/AHA 2005 Practice Guidelines for the management of patients with peripheral arterial disease (lower extremity, renal, mesenteric, and abdominal aortic): a collaborative report from the American Association for Vascular Surgery/Society for Vascular Surgery, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, Society of Interventional Radiology, and the ACC/AHA Task Force on Practice Guidelines (Writing Committee to Develop Guidelines for the Management of Patients With Peripheral Arterial Disease): endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation; National Heart, Lung, and Blood Institute; Society for Vascular Nursing; TransAtlantic Inter-Society Consensus; and Vascular Disease Foundation. [Practice Guideline]

  • Ho L, Phyliky L, Li Y (2006) B-cell chronic lymphocytic leukemia: correlation of clinical stages with angiogenic cytokine expression. Appl Immunohistochem Mol Morphol 14:154–160

    Article  Google Scholar 

  • Inderbitzi R, Buttiker M, Pfluger D, Nachbur B (1992) The fate of bilateral lower limb amputees in end-stage vascular disease. Eur J Vasc Surg 6:321–326

    CAS  Article  Google Scholar 

  • Jarajapu P, Grant B (2010) The promise of cell-based therapies for diabetic complications: challenges and solutions. Circ Res 106:854–869

    CAS  Article  Google Scholar 

  • Kajiguchi M, Kondo T, Izawa H, Kobayashi M, Yamamoto K, Shintani S, Murohara T (2007) Safety and efficacy of autologous progenitor cell transplantation for therapeutic angiogenesis in patients with critical limb ischemia. Circ J 71:196–201

    Article  Google Scholar 

  • Lasala P, Silva A, Gardner A, Minguell J (2010) Combination stem cell therapy for the treatment of severe limb ischemia: safety and efficacy analysis. Angiology 61:551–556

    Article  Google Scholar 

  • Lawall H, Bramlage P, Amann B (2010) Stem cell and progenitor cell therapy in peripheral artery disease. A critical appraisal. [Review]. Thromb Haemost 103:696–709

    CAS  Article  Google Scholar 

  • Mizuno H, Miyamoto M, Shimamoto M, Koike S, Hyakusoku H, Kuroyanagi Y (2010) Therapeutic angiogenesis by autologous bone marrow cell implantation together with allogeneic cultured dermal substitute for intractable ulcers in critical limb ischaemia. J Plast Reconstr Aesthet Surg 63:1875–1882

    Article  Google Scholar 

  • Moscoso I, Barallobre J, de Ilarduya M, Anon P, Fraga M, Calvino R, Domenech N (2009) Analysis of different routes of administration of heterologous 5-azacytidine-treated mesenchymal stem cells in a porcine model of myocardial infarction. Transplant Proc 41:2273–2275

    CAS  Article  Google Scholar 

  • Motukuru V, Suresh R, Vivekanand V, Raj S, Girija R (2008) Therapeutic angiogenesis in Buerger’s disease (thromboangiitis obliterans) patients with critical limb ischemia by autologous transplantation of bone marrow mononuclear cells. J Vasc Surg 48:53S–60S; discussion 60S

  • Nash B, Thomas R, Dormandy A (1991) Therapeutic aspects of white blood cell rheology in severe ischaemia of the leg. J Mal Vasc 16:32–34

  • Omlor W, Bertram H, Kleinschmidt K, Fischer J, Brohm K, Guehring T, Richter W (2010) Methods to monitor distribution and metabolic activity of mesenchymal stem cells following in vivo injection into nucleotomized porcine intervertebral discs. Eur Spine J 19:601–612

    CAS  Article  Google Scholar 

  • Rastegar F, Shenaq D, Huang J, Zhang W, Zhang Q, He C, He C (2010) Mesenchymal stem cells: molecular characteristics and clinical applications. World J Stem Cells 2:67–80

    Article  Google Scholar 

  • Reddy M, Kwak K, Shim J, Jang C, Park J, Park E, Ahn C (2013) A long-term outcome of therapeutic angiogenesis by transplantation of peripheral blood stem cells in critical limb ischemia after interventional revascularization. Diagn Interv Radiol 19:76–80

    Google Scholar 

  • Ruiz-Salmeron R, de la Cuesta-Diaz A, Constantino-Bermejo M, Perez-Camacho I, Marcos-Sanchez F, Hmadcha A, Soria B (2011) Angiographic demonstration of neoangiogenesis after intra-arterial infusion of autologous bone marrow mononuclear cells in diabetic patients with critical limb ischemia. Cell Transplant 20:1629–1639

    Article  Google Scholar 

  • Smadja M, Laurendeau I, Avignon C, Vidaud M, Aiach M, Gaussem P (2006) The angiopoietin pathway is modulated by PAR-1 activation on human endothelial progenitor cells. J Thromb Haemost 4:2051–2058

    CAS  Article  Google Scholar 

  • Suzuki H, Iso Y (2013) Clinical application of vascular regenerative therapy for peripheral artery disease. Biomed Res Int 2013:179730

    Article  Google Scholar 

  • Zhang H, Li M, Li Y, Zhao P, Jing L (2008) Effects of different delivery routes of CD34+ stem cells on cardiac function in the ischemic cardiomyopathy of rats. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 20:214–217

    Google Scholar 

  • Zonta S, De Martino M, Bedino G, Piotti G, Rampino T, Gregorini M, Alessiani M (2010) Which is the most suitable and effective route of administration for mesenchymal stem cell-based immunomodulation therapy in experimental kidney transplantation: endovenous or arterial? Transplant Proc 42:1336–1340

    CAS  Article  Google Scholar 

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Acknowledgment

This work was funded by a grant from the Research Development Fund, Tanta University, Egypt.

Conflict of interest

The authors indicate no potential conflicts of interest.

Author information

Affiliations

  1. Vascular Surgery Unit, Tanta University, Tanta, Egypt

    Ahmed M. Ismail, Hassan Abdel Aty, Adel H. Kamhawy, Mohammed Elhinedy & Mohammed Elwageh

  2. Clinical Pathology Department, Tanta University, Tanta, Egypt

    Said M. Abdou & Amal Ezzat

  3. Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt

    Atef Taha

  4. Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt

    Hoda A. Salem

  5. Faculty of Medicine, Ain Shams University, Cairo, Egypt

    Said Youssif

  6. Immunology and Biotechnology Unit, Zoology Department, Faculty of Science, Center of Excellence in Cancer Research, Tanta University, Tanta, Egypt

    Mohamed L. Salem

Authors
  1. Ahmed M. Ismail
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  2. Said M. Abdou
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  3. Hassan Abdel Aty
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  4. Adel H. Kamhawy
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  5. Mohammed Elhinedy
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  6. Mohammed Elwageh
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  7. Atef Taha
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  8. Amal Ezzat
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  9. Hoda A. Salem
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  10. Said Youssif
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  11. Mohamed L. Salem
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Corresponding author

Correspondence to Mohamed L. Salem.

Additional information

Ahmed M. Ismail and Said M. Abdou have equally contributed to this manuscript.

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Ismail, A.M., Abdou, S.M., Aty, H.A. et al. Autologous transplantation of CD34+ bone marrow derived mononuclear cells in management of non-reconstructable critical lower limb ischemia. Cytotechnology 68, 771–781 (2016). https://doi.org/10.1007/s10616-014-9828-7

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  • DOI: https://doi.org/10.1007/s10616-014-9828-7

Keywords

  • Bone marrow
  • G-CSF
  • Leg ischemia
  • Mobilization
  • CD34+ cells