Concise Review: Cell Therapy for Critical Limb Ischemia: An Integrated Review of Preclinical and Clinical Studies

Abstract

Critical limb ischemia (CLI), the most severe form of peripheral artery disease, is characterized by pain at rest and non-healing ulcers in the lower extremities. For patients with CLI, where the extent of atherosclerotic artery occlusion is too severe for surgical bypass or percutaneous interventions, limb amputation remains the only treatment option. Thus, cell-based therapy to restore perfusion and promote wound healing in patients with CLI is under intense investigation. Despite promising preclinical studies in animal models, transplantation of bone marrow (BM)-derived cell populations in patients with CLI has shown limited benefit preventing limb amputation. Early trials injected heterogenous mononuclear cells containing a low frequency of cells with pro-vascular regenerative functions. Most trials transferred autologous cells damaged by chronic disease that demonstrated poor survival in the ischemic environment and impaired function conferred by atherosclerotic or diabetic co-morbidities. Finally, recent preclinical studies suggest optimized blood vessel formation may require paracrine and/or structural contributions from multiple progenitor cell lineages, angiocrine-secretory myeloid cells derived from hematopoietic progenitor cells, tubule-forming endothelial cells generated by circulating or vessel-resident endothelial precursors, and vessel-stabilizing perivascular cells derived from mesenchymal stem cells. Understanding how stem cells co-ordinate the myriad of cells and signals required for stable revascularization remains the key to translating the potential of stem cells into curative therapies for CLI. Thus, combination delivery of multiple cell types within supportive bioengineered matricies may represent a new direction to improve cell therapy strategies for CLI.

Pro-vascular progenitor cell “exhaustion” in patients with critical limb ischemia (CLI). The human bone marrow microenvironment is a rich reservoir of progenitor cells involved in blood vessel homeostasis and repair. Early myeloid hematopoietic progenitor cells secrete angiocrine signals that stimulate and direct angiogenesis. Circulating and vessel-resident endothelial precursor cells act as the building blocks of blood vessels and inosculate into the vessel wall during vasculogenesis. Multipotent mesenchymal stromal cells (also known as mesenchymal stem cells or MSC) generate vessel wrapping pericytes and smooth muscle cells that stabilize newly formed vessels and act as “conductors of the orchestra” to recruit and co-ordinate the functions of accessory cells (M2 macrophages) implicated in arteriogenic remodeling and activation of collateral vessel perfusion. Unfortunately, in CLI patients with diabetes with atherosclerotic co-morbidities, chronic exposure to oxidative stress, systemic inflammation, lipotoxicity, and glucose toxicity result in regenerative cell depletion and dysfunction within the stem cell pool.

Angiogenesis, Arteriogenesis, Atherosclerosis, Cell therapy, Critical limb ischemia, Endothelial progenitor cells, Hematopoietic progenitor cells, Multipotent mesenchymal stem cells, Peripheral artery disease, Transplantation, Vasculogenesis