Delivery of Placenta-Derived Mesenchymal Stem Cells Ameliorates Ischemia Induced Limb Injury by Immunomodulation

Abstract

Background: Peripheral artery disease (PAD) is a major health burden in the world. Stem cell-based therapy has emerged as an attractive treatment option in regenerative medicine. In this study, we sought to test the hypothesis that stem cell-based therapy can ameliorate ischemia induced limb injury. Methods: We isolated mesenchymal stem cells derived from human placentas (PMSCs) and intramuscularly transplanted them into injured hind limbs. Treatment with PMSCs reduced acute muscle fibers apoptosis induced by ischemia. Results: PMSC treatment significantly enhanced regeneration of the injured hind limb by reducing fibrosis and enhancing running capacity when the animals were subjected to treadmill training. Mechanistically, injected PMSCs can modulate acute inflammatory responses by reducing neutrophil and macrophage infiltration following limb ischemia. ELISA assays further confirmed that PMSC treatment can also reduce pro-inflammatory cytokines, TNF-α and IL-6, and enhance anti-inflammatory cytokine, IL-10 at the injury sites. Conclusion: Taken together, our results demonstrated that PMSCs can be a potential effective therapy for treatment of PAD via immunomodulation.

Placental Stromal Cell Therapy for Experimental Autoimmune Encephalomyelitis: The Role of Route of Cell Delivery

“…Similarly, intraperitoneal implantation of MSCs attenuated EAE via a systemic immunomodulatory effect without infiltrating the CNS [, ]. Intramuscular implantation of placental stromal cells was shown to improve recovery in an ischemia‐induced limb injury model via immunomodulation [] and to mitigate the lethal effects of radiation []. Our study showed that a mixture of maternal and fetal hPSCs were more effective than maternal cells alone [].…”

“…Recent studies have also suggested that stromal cells isolated and expanded from different a Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, and b Laboratory of Radiobiology and Biotechnology, Sharett Institute of Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel layers of the human placenta (human placental stromal cells [hPSCs]) might represent a valid option for cell therapy with significant immunomodulatory properties [12][13][14][15]. This cellular platform is both ethically accepted and easily expandable to produce large batches of an off-the-shelf cell product for allogeneic implantation.…”

Why Should Growth Hormone (GH) Be Considered a Promising Therapeutic Agent for Arteriogenesis? Insights from the GHAS Trial

“…In adults, MSCs are also called resident stem cells and constitute a reserve to replace damaged cells because they are capable of differentiating into a wide variety of cellular types, which is why they have been advocated in tissue-regenerative therapies [146]. MSCs have also been utilized for limb ischemia in both animals and humans with a low level of benefit so far [147][148][149][150]. To improve their potential, some researchers have defended their combination with GH.…”

Safety and Efficacy of Placenta-Derived Mesenchymal Stem Cell Treatment for Diabetic Patients with Critical Limb Ischemia: A Pilot Study

“…On the other hand, immunomodulation effects of MSC treatment for limb ischemia have also previously been demonstrated. Studies have analyzed that P-MSCs inhibit the secretion of pro-inflammatory cytokines, such as IL-6 and TNF-α, whereas they induce the secretion of anti-inflammatory mediators, such as IL-10 [24][25][26]. Moreover, a prolonged inflammatory phase mediated by excessive proinflammatory cytokines is one of the biological characteristics of non-healing foot ulcers [27].…”