(1) Background: The treatment of peripheral arterial disease (PAD) is focused on improving perfusion and oxygenation in the affected limb. Standard revascularization methods include bypass surgery, endovascular interventional procedures, or hybrid revascularization. Cell-based therapy can be an alternative strategy for patients with no-option critical limb ischemia who are not eligible for endovascular or surgical procedures. (2) Aims: The aim of this narrative review was to provide an up-to-date critical overview of the knowledge and evidence-based medicine data on the position of cell therapy in the treatment of PAD. The current evidence on the cell-based therapy is summarized and future perspectives outlined, emphasizing the potential of exosomal cell-free approaches in patients with critical limb ischemia. (3) Methods: Cochrane and PubMed databases were searched for keywords "critical limb ischemia and cell therapy". In total, 589 papers were identified, 11 of which were reviews and 11 were meta-analyses. These were used as the primary source of information, using cross-referencing for identification of additional papers. (4) Results: Meta-analyses focusing on cell therapy in PAD treatment confirm significantly greater odds of limb salvage in the first year after the cell therapy administration. Reported odds ratio estimates of preventing amputation being mostly in the region 1.6-3, although with a prolonged observation period, it seems that the odds ratio can grow even further. The odds of wound healing were at least two times higher when compared with the standard conservative therapy. Secondary endpoints of the available meta-analyses are also included in this review. Improvement of perfusion and oxygenation parameters in the affected limb, pain regression, and claudication interval prolongation are discussed. (5) Conclusions: The available evidence-based medicine data show that this technique is safe, associated with minimum complications or adverse events, and effective.

• Keywords
• adipose tissue, bone marrow, cell therapy, critical limb ischemia, exosome, mesenchymal stem cells, peripheral arterial disease,
• MeSH
• Cell- and Tissue-Based Therapy * MeSH
• Ischemia therapy   MeSH
• Extremities blood supply   MeSH
• Humans MeSH
• Meta-Analysis as Topic MeSH
• Mesenchymal Stem Cells cytology   MeSH
• Endpoint Determination MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND Paracrine factors secreted by adipose-derived stem cells can be captured, fractionated, and concentrated to produce therapeutic factor concentrate (TFC). The present study examined whether TFC effects could be enhanced by combining TFC with a biological matrix to provide sustained release of factors in the target region. MATERIAL AND METHODS Unilateral hind limb ischemia was induced in rabbits. Ischemic limbs were injected with either placebo control, TFC, micronized small intestinal submucosa tissue (SIS), or TFC absorbed to SIS. Blood flow in both limbs was assessed with laser Doppler perfusion imaging. Tissues harvested at Day 48 were assessed immunohistochemically for vessel density; in situ hybridization and quantitative real-time PCR were employed to determine miR-126 expression. RESULTS LDP ratios were significantly elevated, compared to placebo control, on day 28 in all treatment groups (p=0.0816, p=0.0543, p=0.0639, for groups 2-4, respectively) and on day 36 in the TFC group (p=0.0866). This effect correlated with capillary density in the SIS and TFC+SIS groups (p=0.0093 and p=0.0054, respectively, compared to placebo). A correlation was observed between miR-126 levels and LDP levels at 48 days in SIS and TFC+SIS groups. CONCLUSIONS A single bolus administration of TFC and SIS had early, transient effects on reperfusion and promotion of ischemia repair. The effects were not additive. We also discovered that TFC modulated miR-126 levels that were expressed in cell types other than endothelial cells. These data suggested that TFC, alone or in combination with SIS, may be a potent therapy for patients with CLI that are at risk of amputation.

• MeSH
• Extracellular Matrix metabolism   MeSH
• Ischemia genetics   pathology   therapy   MeSH
• Stem Cells cytology   MeSH
• Extremities blood supply   pathology   MeSH
• Rabbits MeSH
• Skin pathology   MeSH
• Laser-Doppler Flowmetry MeSH
• Middle Aged MeSH
• Humans MeSH
• MicroRNAs genetics   metabolism   MeSH
• Cell-Derived Microparticles metabolism   MeSH
• Disease Models, Animal MeSH
• Perfusion MeSH
• Gene Expression Regulation MeSH
• Reperfusion Injury pathology   therapy   MeSH
• Intestinal Mucosa physiology   MeSH
• Intestine, Small physiology   MeSH
• Stem Cell Transplantation * MeSH
• Adipose Tissue cytology   MeSH
• Animals MeSH
• Check Tag
• Rabbits MeSH
• Middle Aged MeSH
• Humans MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• MicroRNAs MeSH