Cell Therapy for Critical Limb Ischemia: Advantages, Limitations, and New Perspectives for Treatment of Patients with Critical Diabetic Vasculopathy

Abstract

Purpose of Review To provide a highlight of the current state of cell therapy for the treatment of critical limb ischemia in patients with diabetes. Recent Findings The global incidence of diabetes is constantly growing with consequent challenges for healthcare systems worldwide. In the UK only, NHS costs attributed to diabetic complications, such as peripheral vascular disease, amputation, blindness, renal failure, and stroke, average £10 billion each year, with cost pressure being estimated to get worse. Although giant leaps forward have been registered in the scope of early diagnosis and optimal glycaemic control, an effective treatment for critical limb ischemia is still lacking. The present review aims to provide an update of the ongoing work in the field of regenerative medicine. Recent advancements but also limitations imposed by diabetes on the potential of the approach are addressed. In particular, the review focuses on the perturbation of non-coding RNA networks in progenitor cells and the possibility of using emerging knowledge on molecular mechanisms to design refined protocols for personalized therapy. Summary The field of cell therapy showed rapid progress but has limitations. Significant advances are foreseen in the upcoming years thanks to a better understanding of molecular bottlenecks associated with the metabolic disorders.

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

“…The molecular mechanisms of new vessel growth may be related to the ability of the injected PB-MNCs to induce vascular remodeling, by paracrine activity (delivering growth factors, cytokines, angiogenic coding, and non-coding RNAs, either free or encapsulated in EVs of small size-exosomes, to soft tissue), as has been suggested by the results in preclinical studies [ 27 – 29 ]. Of note, in line with this hypothesis, we here observed that patients with higher tissue perfusion at the end of the follow-up were characterized by a higher number of small-size EVs.…”

Recent Advances in KEAP1/NRF2-Targeting Strategies by Phytochemical Antioxidants, Nanoparticles, and Biocompatible Scaffolds for the Treatment of Diabetic Cardiovascular Complications

“…The aetiology of ED is different between type 1 DM (T1DM) from T2DM. Indeed, while the insurgence of ED in T1DM is mainly triggered by hyperglycemia alone, in T2DM also insulin resistance and circulating fatty acids play a role (52,72). Considering the effects of hyperglycemia on the endothelium at the molecular level, one of the first steps towards the development of ED is represented by the inhibition of the enzyme glyceraldehyde 3-phosphate dehydrogenase.…”

Co-Delivery of Bioengineered Exosomes and Oxygen for Treating Critical Limb Ischemia in Diabetic Mice

“…17−23 Using exosomes for CLI treatment is superior to growth factor and miRNA therapies since vascularization and muscle regeneration simultaneously require multiple factors, and these can be provided by exosomes but not readily by delivery systems for growth factors and miRNAs. 24 While stem cell-derived exosomes have shown encouraging therapeutic effects for ischemic limbs without diabetes, 17−23,25−27 the efficacy of current exosome therapy for diabetic ischemic limbs is not most favorable. 24 Current exosomes are not tailored with an optimal composition of proangiogenic and promyogenic factors for accelerated vascularization and myogenesis.…”

“…24 While stem cell-derived exosomes have shown encouraging therapeutic effects for ischemic limbs without diabetes, 17−23,25−27 the efficacy of current exosome therapy for diabetic ischemic limbs is not most favorable. 24 Current exosomes are not tailored with an optimal composition of proangiogenic and promyogenic factors for accelerated vascularization and myogenesis. While exosomes can be engineered to contain exogenous cargos necessary for these processes, current approaches typically use soluble biochemicals and growth factors, which may complicate both the exosome composition as well as the resulting therapeutic effects.…”