Cell therapy for critical limb ischemia: Current progress and future prospects

Abstract Introduction Critical limb ischemia (CLI) is the most advanced form of peripheral arterial disease (PAD) characterized by ischemic rest pain and non-healing ulcers. Currently, the standard therapy for CLI is the surgical reconstruction and endovascular therapy or limb amputation for patients with no treatment options. Neovasculogenesis induced by mesenchymal stem cells (MSCs) therapy is a promising approach to improve CLI. Owing to their angiogenic and immunomodulatory potential, MSCs are perfect candidates for the treatment of CLI. The purpose of this study was to determine and compare the in vitro and in vivo effects of allogeneic bone marrow mesenchymal stem cells (BM-MSCs) and adipose tissue mesenchymal stem cells (AT-MSCs) on CLI treatment. Methods For the first step, BM-MSCs and AT-MSCs were isolated and characterized for the characteristic MSC phenotypes. Then, femoral artery ligation and total excision of the femoral artery were performed on C57BL/6 mice to create a CLI model. The cells were evaluated for their in vitro and in vivo biological characteristics for CLI cell therapy. In order to determine these characteristics, the following tests were performed: morphology, flow cytometry, differentiation to osteocyte and adipocyte, wound healing assay, and behavioral tests including Tarlov, Ischemia, Modified ischemia, Function and the grade of limb necrosis scores, donor cell survival assay, and histological analysis. Results Our cellular and functional tests indicated that during 28 days after cell transplantation, BM-MSCs had a great effect on endothelial cell migration, muscle restructure, functional improvements, and neovascularization in ischemic tissues compared with AT-MSCs and control groups. Conclusions Allogeneic BM-MSC transplantation resulted in a more effective recovery from critical limb ischemia compared to AT-MSCs transplantation. In fact, BM-MSC transplantation could be considered as a promising therapy for diseases with insufficient angiogenesis including hindlimb ischemia.

Download Full-text

Cell Therapy in Patients with Critical Limb Ischemia

Stem Cells International ◽

10.1155/2015/931420 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 27

Author(s):

Rita Compagna ◽

Bruno Amato ◽

Salvatore Massa ◽

Maurizio Amato ◽

Raffaele Grande ◽

...

Keyword(s):

Cell Therapy ◽

Critical Limb Ischemia ◽

Limb Ischemia ◽

Tissue Loss ◽

Systematic Analysis ◽

Peripheral Arterial Obstructive Disease ◽

Peripheral Arterial ◽

Cellular Components

Critical limb ischemia (CLI) represents the most advanced stage of peripheral arterial obstructive disease (PAOD) with a severe obstruction of the arteries which markedly reduces blood flow to the extremities and has progressed to the point of severe rest pain and/or even tissue loss. Recent therapeutic strategies have focused on restoring this balance in favor of tissue survival using exogenous molecular and cellular agents to promote regeneration of the vasculature. These are based on stimulation of angiogenesis by extracellular and cellular components. This review article carries out a systematic analysis of the most recent scientific literature on the application of stem cells in patients with CLI. The results obtained from the detailed analysis of the recent literature data have confirmed the beneficial role of cell therapy in reducing the rate of major amputations in patients with CLI and improving their quality of life.

Download Full-text

Long-Term Clinical Outcomes Survey of Bone Marrow-Derived Cell Therapy in Critical Limb Ischemia in Japan

Circulation Journal ◽

10.1253/circj.cj-17-0510 ◽

2018 ◽

Vol 82 (4) ◽

pp. 1168-1178 ◽

Cited By ~ 18

Author(s):

Kazuhisa Kondo ◽

Kenji Yanishi ◽

Ryo Hayashida ◽

Satoshi Shintani ◽

Rei Shibata ◽

...

Keyword(s):

Bone Marrow ◽

Cell Therapy ◽

Clinical Outcomes ◽

Critical Limb Ischemia ◽

Limb Ischemia

Download Full-text

Progenitor Cell Therapy in Patients With Critical Limb Ischemia Without Surgical Options

Annals of Surgery ◽

10.1097/sla.0b013e318153fdcb ◽

2008 ◽

Vol 247 (3) ◽

pp. 411-420 ◽

Cited By ~ 48

Author(s):

Ralf W. Sprengers ◽

Daniel J. Lips ◽

Frans L. Moll ◽

Marianne C. Verhaar

Keyword(s):

Cell Therapy ◽

Critical Limb Ischemia ◽

Progenitor Cell ◽

Limb Ischemia ◽

Surgical Options

Download Full-text

Cell therapy of critical limb ischemia in diabetic patients – State of art

Diabetes Research and Clinical Practice ◽

10.1016/j.diabres.2017.02.028 ◽

2017 ◽

Vol 126 ◽

pp. 263-271 ◽

Cited By ~ 4

Author(s):

Michal Dubský ◽

Alexandra Jirkovská ◽

Robert Bem ◽

Andrea Nemcová ◽

Vladimira Fejfarová ◽

...

Keyword(s):

Cell Therapy ◽

Critical Limb Ischemia ◽

Limb Ischemia ◽

Diabetic Patients ◽

State Of Art

Download Full-text

Current Status of Cell-Based Therapy in Patients with Critical Limb Ischemia

International Journal of Molecular Sciences ◽

10.3390/ijms21238999 ◽

2020 ◽

Vol 21 (23) ◽

pp. 8999

Author(s):

Frantisek Jaluvka ◽

Peter Ihnat ◽

Juraj Madaric ◽

Adela Vrtkova ◽

Jaroslav Janosek ◽

...

Keyword(s):

Cell Therapy ◽

Critical Limb Ischemia ◽

Evidence Based Medicine ◽

Odds Ratio ◽

Limb Ischemia ◽

Current Evidence ◽

Evidence Based ◽

Cell Based Therapy ◽

Meta Analyses ◽

Based Medicine

(1) Background: The treatment of peripheral arterial disease (PAD) is focused on improving perfusion and oxygenation in the affected limb. Standard revascularization methods include bypass surgery, endovascular interventional procedures, or hybrid revascularization. Cell-based therapy can be an alternative strategy for patients with no-option critical limb ischemia who are not eligible for endovascular or surgical procedures. (2) Aims: The aim of this narrative review was to provide an up-to-date critical overview of the knowledge and evidence-based medicine data on the position of cell therapy in the treatment of PAD. The current evidence on the cell-based therapy is summarized and future perspectives outlined, emphasizing the potential of exosomal cell-free approaches in patients with critical limb ischemia. (3) Methods: Cochrane and PubMed databases were searched for keywords “critical limb ischemia and cell therapy”. In total, 589 papers were identified, 11 of which were reviews and 11 were meta-analyses. These were used as the primary source of information, using cross-referencing for identification of additional papers. (4) Results: Meta-analyses focusing on cell therapy in PAD treatment confirm significantly greater odds of limb salvage in the first year after the cell therapy administration. Reported odds ratio estimates of preventing amputation being mostly in the region 1.6–3, although with a prolonged observation period, it seems that the odds ratio can grow even further. The odds of wound healing were at least two times higher when compared with the standard conservative therapy. Secondary endpoints of the available meta-analyses are also included in this review. Improvement of perfusion and oxygenation parameters in the affected limb, pain regression, and claudication interval prolongation are discussed. (5) Conclusions: The available evidence-based medicine data show that this technique is safe, associated with minimum complications or adverse events, and effective.

Download Full-text