Therapeutic strategies for cell-based neovascularization in critical limb ischemia

Abstract

Critical limb ischemia (CLI) causes severe ischemic rest pain, ulcer, and gangrene in the lower limbs. In spite of angioplasty and surgery, CLI patients without suitable artery inflow or enough vascular bed in the lesions are often forced to undergo amputation of a major limb. Cell-based therapeutic angiogenesis has the potential to treat ischemic lesions by promoting the formation of collateral vessel networks and the vascular bed. Peripheral blood mononuclear cells and bone marrow-derived mononuclear cells are the most frequently employed cell types in CLI clinical trials. However, the clinical outcomes of cell-based therapeutic angiogenesis using these cells have not provided the promised benefits for CLI patients, reinforcing the need for novel cell-based therapeutic angiogenesis strategies to cure untreatable CLI patients. Recent studies have demonstrated the possible enhancement of therapeutic efficacy in ischemic diseases by preconditioned graft cells. Moreover, judging from past clinical trials, the identification of adequate transplant timing and responders to cell-based therapy is important for improving therapeutic outcomes in CLI patients in clinical settings. Thus, to establish cell-based therapeutic angiogenesis as one of the most promising therapeutic strategies for CLI patients, its advantages and limitations should be taken into account.

Possibility of Injecting Adipose-Derived Stromal Vascular Fraction Cells to Accelerate Microcirculation in Ischemic Diabetic Feet: A Pilot Study

“…The potential of stem cells has been explored to overcome limitations of conventional revascularization methods such as PTA and bypass surgery (4, 5, 9). SVF cells consist of a heterogeneous population of cells, including adipose stromal, hematopoietic stem, progenitor, and endothelial cells (15).…”

Protein disulfide isomerase as a prosurvival factor in cell therapy for muscular and vascular diseases

“…Critical limb ischemia is characterized by markedly reduced blood flow to the extremities and is the most severe and frequent form of peripheral artery disease. Cell therapy represents a promising therapeutic approach for vascular tissue regeneration for ischemic diseases [ 67 ]. However, clinical trials indicate consistently modest long-term improvements due, at least in part, to poor survival of transplanted cells [ 68 , 69 ].…”

Ghrelin, MicroRNAs, and Critical Limb Ischemia: Hungering for a Novel Treatment Option

“…However, to date, there is a clear disparity between pre-clinical trials and large randomized control trials. Few clinical trials report long-term positive effects or clinically significant results ( 18 , 41 ). These disappointing findings with current angiogenic agents can be attributed to numerous factors, including suboptimal delivery strategies ( 42 ), disease mediated dysfunction ( 43 ), methodological differences, and pre-clinical models which lack common CLI risk factors ( 41 ).…”

“…Angiogenic agents, such as gene or cell therapy, have been the focus of investigation, with the aim of inducing a pro-angiogenic milieu in the affected ischemic limb. Regrettably, the results from clinical trials using such agents have shown little clinical benefit regarding primary outcome measures (i.e., patency, amputation-free survival, major limb adverse effects) ( 18 – 20 ). This highlights both the complexity of therapeutic angiogenesis and the need to develop new agents for the management of CLI.…”