Discussion
lower extremity vascular disease, toxicity, amputation, ischemia, atherosclerotic, claudication, fibrosis, pain, infection, diabetic, Buerger's disease and ischemic limb disease, decreases pain, newborn cell immaturity, injury to the nerves, ulcer, injuries, presenting karyotypic aberrations
ARTERIAL OBSTRUCTION, CARDIOVASCULAR DISEASE, CARDIOVASCULAR DISEASES, PROLIFERATION, LIMB ISCHEMIA, DISEASES, ISCHEMIA, FIBROSIS, PAD, INFECTION, ISCHEMIC ULCERS, CHRONIC RENAL DISEASE, ULCER, COMPLICATIONS, CHRONIC LIMB-THREATENING ISCHEMIA
Patients afflicted with CLTI have a poor quality of life and a high rate of limb loss [In this context, new strategies such as regenerative medicine have enabled the development of therapeutic angiogenesis through recombinant proteins, gene transfer, or stem cells [Initial preclinical and small pilot clinical studies have demonstrated promising effects of cell therapy in PAD and CLTI. Particularly, the results of these studies suggest that most stem cell therapies can increase blood flow at the transplantation site by promoting angiogenesis and neo-vascularization through a direct effect of the administered cells on the vasculature, or by secretion of pro-angiogenic factors and modulation of the local immune response, which prevents amputation in patients with CLTI [A crucial concern with stem cell therapy is its safety profile. Nevertheless, most of the published preclinical and clinical trials have reported that stem cells are safe to treat numerous injuries and diseases, including lower extremity vascular disease [The present study did not detect serious AEs, like malignancy, infection, organ system complications, or acute toxicity related to auto-BM-MNC or allo-WJ-MSC injections used to treat CLTI. In contrast, the participants receiving the placebo solution presented less ulcer healing and higher amputation rates. These findings were consistent with the evidence from numerous clinical trials that evaluated the safety of BM-MNC or MSC-based therapy in CLTI [Regarding the effectiveness profile of the cell-based therapy, few clinical studies have aimed to compare the efficacy of different stem cells in treating CLTI in diabetic patients.Several studies have reported that diabetic patients showed both a marked depletion of CD34Although our results strongly indicate that auto-BM-MNC and allo-WJ-MSCs increase limb’s blood flow and improve claudication symptoms of limb ischemia, we observe more promising results with allo-WJ-MSCs than auto-BM-MNC. Remarkably, in the clinical parameters that were evaluated, we observed an improvement in Rutherford’s classification, a significant increase in TcPOOn the other hand, a number of preclinical and clinical studies have not demonstrated the clear benefits of auto-BM-MNC in various cardiovascular diseases [Furthermore, the expected therapeutic angiogenesis using autologous BM-derived stem cells displays several disadvantages. Among them are the considerably limited amount of bone marrow obtained, and the procedure is painful for the patients. Besides, it may require general anesthesia, which can be life-threatening for patients with CLTI, who are already at elevated risk for difficulties due to their advanced age and cardiovascular disease. Similarly, the migration of circulating BM-derived stem cells is inefficient and significantly lower in patients with CLTI than in healthy subjects due to extended pro-inflammatory stimuli [Recently, different studies have shown that autologous BM-MSC transplantation in patients with CLTI may have a risk of presenting karyotypic aberrations. Nonetheless, it is still not entirely understood if these abnormalities are innate of patients’ cells or have been originated during cell culture [In this regard, studies that used Buerger's disease and ischemic limb disease animal models, demonstrated that umbilical cord blood-derived MSCs (UCB-MSCs) regenerated arterioles and promoted the differentiation into, UCB-MSCs offer various advantages due to (i) the newborn cell immaturity compared to adult stem cells and (ii) the ability to prevent immune reactions. In addition, the UCB-MSCs are less vulnerable to the attack of the recipient’s body than BM-derived stem cells. Several clinical trials have demonstrated that intramuscular administration of UCB-MSCs conduces to arterial reconstruction or prevention of arterial obstruction, decreases pain at rest and speeds up the healing process of ischemic ulcers. These studies proposed that growth factors or pain releasers secreted by implanted stem cells before vessel generation in ischemic regions, may be responsible for pain relief [Another clinical trial that used UCB-MSCs demonstrated the creation of new collateral arteries by computerized tomography angiography; this change was more apparent in the microvascular network than in the macrovascular network. Furthermore, compared to pre-treatment levels, the percentages of CD3The MSC’s therapeutic role in patients with CLTI has been attributed to their unique biological features. MSCs can promote angiogenesis, reduce fibrosis, restore collagen balance, decrease immune cell activities, and undergo EC differentiation [Different studies have shown that the MSC involvement in maintaining structures of neovessels in vivo is through several molecular pathways. Among those, the Wnt pathways are essential in adjusting MSC differentiation, proliferation, and migration. WNT4 activation in MSC increases blood flow. In particular, frizzled-related protein-1, a Wnt modulator secreted by MSCs, promotes angiogenesis by increasing MSC integration into neovessels, which implies that specific molecular targets are responsible for MSC engraftment into the vasculature, while TGF-β signaling regulates MSC differentiation into pericytes [Regarding the best form of cell administration, most therapeutic trials addressing CLTI have focused on intramuscular cell administration as a more feasible and less harmful approach, demonstrating safety and effectiveness [Other administration routes are intravascular, which is more invasive and harmful since involves administering contrast materials that are injected into a vein, but is not recommended in patients with chronic renal disease [IA injection entails the danger of injury to the nerves and arteries, vessel wall dissection, and dislodgment of atherosclerotic plaques [Another point of concern is the cell dosage to apply, which can vary according to the cell type/source [On the other hand, the severity of ischemia in patients that are candidate for cellular treatment is a critical aspect to consider in clinical trials. In our study, the participants were in Rutherford’s stages 3–5, and responded effectively to the cellular treatment. This finding agrees with other studies, such as Walter et al., who reported that individuals with Rutherford’s stages 4–5 did respond to cellular treatment, but those with stage 6 did not [We designed our study primarily as a pilot study and proof of concept, and even though the sample size was small, one of the limitations of this study, we saw a significant clinical improvement in the auto-BM-MNC and allo-WJ-MSC-treated participants compared with the placebo group. Nevertheless, according to our research, allo-WJ-MSCs can rival auto-BM-MNC because of less invasive extraction approaches. Therefore, it is recommended to do a multi-centric randomized phase II clinical trial, which includes a large number of subjects from different geographic places, to gather more information about auto-BM-MNC and allo-WJ-MSC effectiveness. Nevertheless, our results provide new knowledge about the safety and efficacy of auto-BM-MNC and allo-WJ-MSC in diabetic patients with chronic limb-threatening ischemia.Finally, stem cell treatment may sometimes encounter ethical obstacles or biological restrictions. Thus, in recent years, it has been thought that the released secretomes, composed of biologically active molecules (growth factors, cytokines and chemokines, angiogenic factors, extracellular matrix proteins, proteases, and genetic material secreted from stem cells), have revealed a considerable capacity for repair and regeneration of damaged cell membranes, or induce the secretion of surrounding tissues could reveal a new approach for the cell-free treatment [