Fetal progenitor cells for treatment of chronic limb ischemia.

Am J Stem Cells 2024;13(3):169-190 www.AJSC.us /ISSN:2160-4150/AJSC0154107 Original Article Fetal progenitor cells for treatment of chronic limb ischemia Oleksandr Kukharchuk1, Abhijit Bopardikar2, Padma Priya Anand Baskaran1, Andrii Kukharchuk1, Rohit Kulkarni1, Ranjit Ranbhor3 ReeLabs Pvt. Ltd., 1st Floor, KK Chambers, Sir P.T. Rd., Azad Maidan, Fort, Mumbai 400001, India; 2ReeLabs Inc., 16192 Coastal Hwy, Lewes, DE 19958, USA; 3No. 270 Baldwin Road, Parsippany, NJ 07054, USA 1 Received October 25, 2023; Accepted May 6, 2024; Epub June 15, 2024; Published June 30, 2024 Abstract: Objectives: This study investigated the therapeutic potential of fetal progenitor cells (FPCs) in the treatment of chronic non-healing wounds and ulcers associated with chronic limb ischemia (CLI). The research aimed to elucidate the mechanism of action of FPCs and evaluate their efficacy and safety in CLI patients. Methods: The researchers isolated FPCs from aborted human fetal liver, brain, and skin tissues and thoroughly characterized them. The preclinical phase of the study involved assessing the effects of FPCs in a rat model of CLI. Subsequently, a randomized controlled clinical trial was conducted to compare the efficacy of FPCs with standard treatment and autologous bone marrow mononuclear cells in CLI patients. The clinical trial lasted 12 months, with a follow-up period of 24-36 months. The primary outcomes included wound healing, frequency of major and minor amputations, pain reduction, and the incidence of complications. Secondary outcomes involved changes in local hemodynamics and histological, ultrastructural, and immunohistochemical assessments of angiogenesis. Results: In the animal model, FPC treatment significantly enhanced angiogenesis and accelerated healing of ischemic wounds compared to controls. The clinical trial in CLI patients demonstrated that the FPC therapy achieved substantially higher rates of complete wound closure, prevention of major amputation, pain reduction, and improvement in ankle-brachial index compared to control groups. Notably, the study reported no serious adverse events. Conclusions: FPC therapy exhibited remarkable efficacy in promoting the healing of ischemic wounds, preventing amputation, and improving symptoms and quality of life in patients with CLI. The proangiogenic and provasculogenic effects of FPCs may be attributed to their ability to secrete specific growth factors. These findings provide new insights into the development of cellular therapeutic angiogenesis as a promising approach for the treatment of peripheral arterial diseases. Keywords: Chronic limb ischemia, fetal progenitor cells, bone marrow mononuclear cells, regenerative medicine Introduction Chronic limb ischemia (CLI), the most advanced stage of peripheral arterial disease (PAD), represents a significant unmet medical need with high rates of morbidity, mortality, and limb loss. Atherosclerosis causes blockages in the arteries supplying blood to the legs and arms, which can worsen over time, leading to significantly reduced blood flow and the development of CLI [1]. Key mechanisms underlying this progression include atherosclerotic plaque build-up, inflammation, thrombosis, collateral artery failure, and tissue damage [2]. The prevalence of CLI remains challenging to determine due to the heterogeneity of available data. However, estimates suggest that CLI affects approximately 10% of all PAD patients, who are at high risk of death, with reported 4-year mortality rates ranging from 18.9% to 63.5%, depending on the Rutherford classification [3]. Most CLI patients require hospitalization for surgical or endovascular interventions, while others need frequent outpatient visits to assess disease stability or progression and require dressing changes for non-healing ulcers. In 2014, the annual cost burden for the hospitalization of PAD patients in the United States was approximately USD 6.31 billion [4]. Despite advances in revascularization techniques, surgical or endovascular revascularization may not be feasible in some patients due to https://doi.org/10.62347/MZKI8393 Fetal progenitor cells for chronic limb ischemia treatment significant comorbidities which leads to a reduction in life expectancy [5]. The Global Vascular Guidelines have improved the management of CLI patients with evidence-based revascularization (EBR), aiming to identify patients for whom revascularization would only increase the risks of adverse events rather than provide real benefits. The therapeutic choice should avoid unnecessary revascularization and focus on the patient as a whole, with improved risk-modifying therapy potentially being the key to future PAD management. A non-negligible proportion of CLI patients are unsuitable for revascularization due to anatomical or physiological reasons, a subgroup defined as “no-option CLI” [6]. This concept is based on the assumption of potential successful revascularization in CLI patients without a suitable target arterial pathway and no visible arterial circulation in the foot (desert foot). This type of arterial disease is more common in patients with diabetes and end-stage renal disease and was previously the main criterion for performing major amputations. However, the development of new technologies and devices, especially in the endovascular field, has contributed to the re-emergence of no-option CLI as a new area of research before considering major amputations. The true incidence and prevalence of no-option CLI patients remain unknown due to the lack of epidemiological studies, but no-option CLI is known to be associated with ischemic heart disease, end-stage renal disease, and heart failure. The primary goals for these patients are relieving ischemic pain, healing ulcers, avoiding limb loss, improving quality of life, and prolonging survival. Treatment for CLI primarily consists of risk factor mitigation, including control of cholesterol and glycemic levels, smoking cessation, and endovascular or open surgical revascularization when feasible. However, nearly 20-40% of patients may not respond to or have failed standard medical therapy or are unsuitable for revascularization [7-9]. Given the high economic burden, decreased quality of life, and poor survival associated with CLI, regenerative therapies aimed at promoting neovascularization to improve wound healing and limb salvage hold significant promise, highlighting the critical need for novel vascular regenerative therapies [10]. 170 Cell therapy, particularly using mesenchymal stem cells (MSCs), has emerged as a promising regenerative strategy for stimulating therapeutic angiogenesis in CLI. MSCs play a crucial role in wound healing and angiogenesis due to their potential for multilineage cell differentiation, ability to secrete soluble factors and exosomes (paracrine functions), and immunomodulatory and antibacterial activity [11]. A study by Liotta et al. [12] introduced the concept of autol (...truncated)