Emerging roles of mesenchymal stem cell therapy in patients with critical limb ischemia

Abstract

Critical limb ischemia (CLI), the terminal stage of peripheral arterial disease (PAD), is characterized by an extremely high risk of amputation and vascular issues, resulting in severe morbidity and mortality. In patients with severe limb ischemia with no alternative therapy options, such as endovascular angioplasty or bypass surgery, therapeutic angiogenesis utilizing cell-based therapies is vital for increasing blood flow to ischemic regions. Mesenchymal stem cells (MSCs) are currently considered one of the most encouraging cells as a regenerative alternative for the surgical treatment of CLI, including restoring tissue function and repairing ischemic tissue via immunomodulation and angiogenesis. The regenerative treatments for limb ischemia based on MSC therapy are still considered experimental. Despite recent advances in preclinical and clinical research studies, it is not recommended for regular clinical use. In this study, we review the immunomodulatory features of MSC besides the current understanding of different sources of MSC in the angiogenic treatment of CLI subjects and their potential applications as therapeutic agents. Specifically, this paper concentrates on the most current clinical application issues, and several recommendations are provided to improve the efficacy of cell therapy for CLI patients.

Keywords: Angiogenesis; Cell therapy; Clinical trials; Critical limb ischemia; Hindlimb ischemia; Mesenchymal stem cells; Peripheral arterial disease.

Fig. 1

Major sources of mesenchymal stem cells (MSCs) and potential mechanisms of MSCs therapy in limb ischemia. MSCs are isolable from several sources. They restore tissue function and repair ischemic tissue via immunomodulation and angiogenesis. MSCs suppress inflammation and promote immunomodulation by secreting immunomodulatory cytokines, which stimulate the induction of M2 macrophages and increase the number of circulating regulatory T cells, resulting in an increase in interleukin IL-10 and resolution of inflammation. Additionally, MSCs release factors that promote angiogenesis directly. The possible mechanism by which MSCs mediate angiogenesis via direct dedifferentiation or through paracrine effects on effector cells such as smooth muscle cells, endothelial cells, and pericytes in the formation of mature vessels. ADT adipose tissue, BM bone marrow, CLI critical limb ischemia, ECs endothelial cells, iDC immature dendritic cell, mDC mature dendritic cell, MO monocyte, MQ-M₂ macrophage M₂, MSC mesenchymal stem cells, NK natural killer cells, PB peripheral blood, SMCs smooth muscle cells, T-reg regulatory T cell, UCB umbilical cord blood