Autologous cell therapy in diabetes‑associated critical limb ischemia: From basic studies to clinical outcomes (Review)

Abstract

Cell therapy is becoming an attractive alternative for the treatment of patients with no-option critical limb ischemia (CLI). The main benefits of cell therapy are the induction of therapeutic angiogenesis and neovascularization that lead to an increase in blood flow in the ischemic limb and tissue regeneration in non-healing cutaneous trophic lesions. In the present review, the current state of the art of strategies in the cell therapy field are summarized, focusing on intra-operative autologous cell concentrates in diabetic patients with CLI, examining different sources of cell concentrates and their mechanisms of action. The present study underlined the detrimental effects of the diabetic condition on different sources of autologous cells used in cell therapy, and also in delaying wound healing capacity. Moreover, relevant clinical trials and critical issues arising from cell therapy trials are discussed. Finally, the new concept of cell therapy as an adjuvant therapy to increase wound healing in revascularized diabetic patients is introduced. Contents 1. Introduction 2. Cell therapy: Unfractioned mixed cell population concentrate or pure stem/progenitor cell concentrate 3. Diabetes impairs the angiogenic and regenerative capacity of autologous cell therapy 4. Clinical trials in no-option patients 5. Conclusions and future perspectives

Results of a prospective observational study of autologous peripheral blood mononuclear cell therapy for no-option critical limb-threatening ischemia and severe diabetic foot ulcers

“…We here provide new evidence in support of autologous PB-MNC therapy in no-option diabetic CLTI. PB-MNC treatment as adjuvant therapy in diabetic patients was proposed by Persiani et al [ 34 ] and discussed in a recent review on autologous cell therapy [ 35 ]. PB-MNCs treatment may find application in nondiabetic contexts.…”

Estrogen‐related receptor alpha is anAMPK‐regulated factor that promotes ischemic muscle revascularization and recovery in diet‐induced obese mice

“…Although the capillary density is restored in the TG‐DIO TA, return to normal hemodynamics may not be complete due to other effects of diet‐induced obesity (e.g., changes in vascular tone). Another reason might be the selective activation of ERRα in the skeletal muscle, and not in other cell types such as endothelial cells, pericytes, and immune cells, which are also involved in regulating angiogenesis in limb ischemia, 40 and where ERRα could orchestrate a more global angiogenic control. Another reason might be that the overexpressed ERRα is an apo receptor, which as much as is constitutively active, can be further stimulated with co‐factors or potential ligands to elicit full transcriptional activation 12 .…”

The Immune-Centric Revolution in the Diabetic Foot: Monocytes and Lymphocytes Role in Wound Healing and Tissue Regeneration—A Narrative Review

“…Interestingly, in the subset of diabetic patients 65.5% of wounds with the macrophage treatment healed, while only 15.4% of healing was observed in the standard care group [114]. Magenta et al recently published an extensive review on autologous cell therapy from different tissue sources (blood, bone marrow, and adipose tissue) to treat critical limb ischemia in diabetic patients, reporting data from basic science to clinical trials [115]. Autologous cell therapy, in particular, autologous Peripheral Blood Mononuclear Cells (PBMNC), based on monocytes/macrophages and lymphocytes represent an interesting strategy to treat non-option critical limb patients and diabetic foot patients [116][117][118][119][120][121].…”