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. Stem Cells 2018;36:161-171.

Thermosensitive, fast gelling, photoluminescent, highly flexible, and degradable hydrogels for stem cell delivery

“…MSCs have been used for myocardial infarction therapy and ischemic limb treatment [1, 93–96]. Studies have shown that MSCs can improve cardiac function, and promote vascularization in ischemic limbs [1, 93–96]. The major contribution of MSCs lies in their paracrine effects which provide multiple growth factors necessary for cell survival and angiogenesis.…”

“…The major contribution of MSCs lies in their paracrine effects which provide multiple growth factors necessary for cell survival and angiogenesis. These growth factors include but are not limited to IGF-1, HGF, bFGF, VEGF, and PDGF [1, 93–96]. Approaches that stimulate MSC paracrine effects are attractive as they may increase therapeutic efficacy.…”

“…Ischemic cardiovascular diseases such as myocardial infarction (MI) and critical limb ischemia (CLI) affect millions of people in the world [1, 2]. The ischemic cardiac tissue and limbs are characterized by extensive cell death, poor blood perfusion, and ischemic environment.…”

Promotion of Cell Migration into a Hydrophobically modified Alaska Pollock Gelatin‐Based Hydrogel

“…After the purification, precipitates were vacuum dried at room temperature (20-30 °C). As the gelatin sample control, original ApGltn (Org-ApGltn) was also synthesized without adding hexanal and 2-picBH 3 . The modification ratio of the hexyl group was quantified by the TNBS method, [24][25][26] comparing absorbance between Organd C6-ApGltn.…”

Collateral development and arteriogenesis in hindlimbs of domestic swine after ligation of arterial inflow

“…We believe that the present report can serve as a reference for future studies on novel therapeutic interventions that would enhance collateral growth. For example, a porcine model could help in the optimization of delivery methods, dosing and efficacy testing of experimental arteriogenic treatments, including cell-based therapies [23,[25][26][27][28].…”