Understanding mechanisms of the umbilical cord-derived multipotent mesenchymal stromal cell-mediated recovery enhancement in rat model of limb ischemia

Abstract

Umbilical cord-derived multipotent mesenchymal stromal cells (UC-MMSCs) are considered as a strong candidate for cell therapy of lower limb ischemia. Sustained calf muscle ischemia with aseptic inflammatory response was induced in Sprague-Dawley rats by excision of femoral and popliteal arteries. uC-MSCs were injected into the calf muscle on day 7 after surgery. The animals were sacrificed on days 3, 10, and 30 after transplantation. Animals responded to the transplantation by temporary improvement in their locomotor function as assessed by the rota-rod performance test. Measured size of the lesions was significantly smaller in the experimental group than in the control group at all time points throughout the observation. The transplantation stimulated angiogenic processes on day 10 after transplantation. Living transplanted cells were traced for up to 30 days after transplantation, during which time they migrated to the damaged area to be partially eliminated by host macrophages; none of them differentiated into endothelial or smooth muscle cells of blood vessels. Additionally, the transplantation led to the predominance of activated pro-angiogenic and anti-inflammatory M2 macrophages by inhibiting the CD68+ macrophage infiltration and stimulating the CD206+ macrophage activation at the site of injury. A single intramuscular injection of allogeneic umbilical cord-derived mesenchymal stromal cells reproducibly facilitated recovery of structural and functional properties of surgically ischemized calf muscles in a rat. No differentiation of the transplanted cells in vivo was observed. The transplantation negatively regulated inflammation and enhanced tissue repair chiefly by modulating local patterns of macrophage activation.

Implantable Therapeutic Reservoir Systems for Diverse Clinical Applications in Large Animal Models

“…Intraperitoneal infusion with CAR T‐cells can also reduce tumor burden in animal models of peritoneal carcinomatosis, [ 18 ] with repeat dosing leading to an improved response. [ 19,20 ] Intramuscular delivery of cells to skeletal muscle has also been used for treatment of critical limb ischemia [ 21–24 ] and skeletal muscle regeneration, [ 25–27 ] obviating the need for localized delivery of cells to intramuscular targets. Cardiac tissue may also benefit from direct cell delivery compared to systemic administration; for example, implantation of stem cells in the heart leads to improved retention [ 28 ] and cardiac function after myocardial infarction via paracrine mediators, [ 11–13 ] and several studies in rodents suggest repeated dosing provides functional improvement compared to a single infusion of cells.…”