Introduction
DLTs, CLI, PAD, lower-extremity ischemia, toxicities, gangrene, atherosclerotic, pain, extracranial carotids, non-atherosclerotic
PERIPHERAL ARTERY DISEASE, ARTERIAL DISORDERS, GANGRENE, PAD, CRITICAL LIMB ISCHEMIA
Peripheral artery disease (PAD), except for aortic and coronary involvement, includes all arterial disorders. It is mainly associated with extracranial carotids, upper extremity arteries, renal and mesenteric arteries, and lower limb arteries [Critical limb ischemia (CLI), the most severe form of PAD, results in ischemic rest pain, unhealed wounds, gangrene, and limb amputations. Endovascular revascularization or open surgery is the current standard treatment for improving blood flow to affected limbs [Vascular regeneration processes, such as angiogenesis and arteriogenesis, occur in ischemic lesions in healthy tissues. Yet, this phenomenon does not occur in CLI [In preclinical studies employing animal models of lower-extremity ischemia, autologous and allogeneic MSCs produced from various sources, including bone marrow, adipose tissue, and prenatal sources, have been beneficial [MSCs improve the endurance of pre-existing blood vessels in co-culture with ECs in a dose-dependent manner [The placenta is a highly vascular tissue that receives several angiogenesis-stimulating impulses. This feature makes it an ideal milieu for signals that promote angiogenesis. Placenta-derived mesenchymal stem cells (P-MSCs) exhibit morphological features nearly identical to those of other MSCs, which are detected in the vascular niche of the placenta [P-MSCs are an excellent example of fetal stem cells that have been suggested as substitutes for medical applications [Similar to other MSCs, P-MSCs exhibit a limited level of HLA-A, HLA-B, and HLA-C molecules, which reduces their immunogenicity and increases their suitability for transplantation. P-MSCs cause pro-inflammatory M1 cells to transform into anti-inflammatory M2 cells. He S.et al. showed that placental mesenchymal cells (PDA-002) injected into a mouse model of HLI increased M2 anti-inflammatory macrophages in ischemic tissue. They also induce the cytokine profile and gene expression of Th2 lymphocytes. These findings indicate that the increase in angiogenesis of PDA-002 cells occurs through an immunomodulatory mechanism in which T lymphocytes play a key role in the differentiation and reprogramming of macrophages toward the M2 type [Additionally, P-MSCs expressing HLA-G inhibit T cell development [In this study, owing to the distinguishing features of P-MSCs in regenerating ischemic tissue and regaining tissue function through immunomodulation and angiogenesis, the therapeutic benefit of P-MSCs was utilized for subjects with CLI. This is a report of a dose-escalation phase 1 study (IRCT ID: IRCT20210221050446N1) to evaluate the tolerability and identify the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of intramuscular P-MSC delivery in nine atherosclerotic and non-atherosclerotic patients with CLI.