Mesenchymal stem cell-based therapy for non-healing wounds due to chronic limb-threatening ischemia: A review of preclinical and clinical studies

Abstract

Progressive peripheral arterial disease (PAD) can result in chronic limb-threatening ischemia (CLTI) characterized by clinical complications including rest pain, gangrene and tissue loss. These complications can propagate even more precipitously in the setting of common concomitant diseases in patients with CLTI such as diabetes mellitus (DM). CLTI ulcers are cutaneous, non-healing wounds that persist due to the reduced perfusion and dysfunctional neovascularization associated with severe PAD. Existing therapies for CLTI are primarily limited to anatomic revascularization and medical management of contributing factors such as atherosclerosis and glycemic control. However, many patients fail these treatment strategies and are considered “no-option,” thereby requiring extremity amputation, particularly if non-healing wounds become infected or fulminant gangrene develops. Given the high economic burden imposed on patients, decreased quality of life, and poor survival of no-option CLTI patients, regenerative therapies aimed at neovascularization to improve wound healing and limb salvage hold significant promise. Cell-based therapy, specifically utilizing mesenchymal stem/stromal cells (MSCs), is one such regenerative strategy to stimulate therapeutic angiogenesis and tissue regeneration. Although previous reviews have focused primarily on revascularization outcomes after MSC treatments of CLTI with less attention given to their effects on wound healing, here we review advances in pre-clinical and clinical studies related to specific effects of MSC-based therapeutics upon ischemic non-healing wounds associated with CLTI.

Novel Gene-Modified Mesenchymal Stem Cell Therapy Reverses Impaired Wound Healing in Ischemic Limbs

“…Both the MSC secretome as well as the increase in tissue neovascularization and perfusion likely contribute to the observed differences in epithelialization and collagen abundance observed in mice treated with E-selectin-modified MSCs. A significant limitation to the efficacy of many MSC-based therapeutics is the effective engraftment and survival of MSCs at sites of administration, which is particularly challenging in ischemic/hypoxic tissue sites 14 . E-selectin modification of MSCs resulted in a greater number of cells present in wound tissue at POD7 compared with control cells.…”

“…Another deficit associated with ischemic wound healing is the reduction in keratinocyte and fibroblast proliferation required for re-epithelialization and collagen deposition 14,37 . Although the precise mechanism remains to be elucidated, E-selectin-modified MSCs showed a substantial increase in the rate of re-epithelialization and the total amount of collagen deposition in ischemic wounds compared with control MSCs.…”

“…Given that local MSC E-selectin-GFP therapy demonstrated reassuring biosafety results with no aberrant alterations in any serologic hematologic, renal, or hepatic function parameters, future preclinical testing in similar animal models should be undertaken. An additional challenge of current clinical trials for cell-based therapeutics for CLTI patients is the accrual of sufficient patient numbers due to the advent of endovascular options to treat disease 14 . As a result, we envision this cell therapy platform in testing not only for patients deemed “no-option” after endovascular failure but also as a potential adjunctive therapy for patients with multifocal vascular disease, diabetic microangiopathy, and for patients likely to fail initial therapy such as those with inherited disorders of cholesterol transport and storage or those with inflammatory and thrombotic microvascular diseases.…”

“…Specifically, autologous MSC populations harvested from patients with CLTI have suffered from reduced functional capacity due to comorbid conditions (diabetes, renal disease, etc.) and heterogeneity in administered cells 14 . As a result, modifications of MSCs to increase therapeutic potency are needed to provide hope for future cell-based therapies.…”

Standardisation is the key to the sustained, rapid and healthy development of stem cell‐based therapy

“…67 At the same time, limitations to these methods should also be considered, as they may induce off-target toxicity and other unintended effects on stem cells, as well as lead to transient expression of molecular targets. 67,68 In order to target stem cells to specific tissues, researchers have developed a variety of corresponding stem cell delivery devices. The most studied ones are devices that apply stem cells to the heart.…”