Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program.

The mitochondria of various tissues from mice, naked mole rats (NMRs), and bats possess two mechanistically similar systems to prevent the generation of mitochondrial reactive oxygen species (mROS): hexokinases I and II and creatine kinase bound to mitochondrial membranes. Both systems operate in a manner such that one of the kinase substrates (mitochondrial ATP) is electrophoretically transported by the ATP/ADP antiporter to the catalytic site of bound hexokinase or bound creatine kinase without ATP dilution in the cytosol. One of the kinase reaction products, ADP, is transported back to the mitochondrial matrix via the antiporter, again through an electrophoretic process without cytosol dilution. The system in question continuously supports H <sup>+</sup> -ATP synthase with ADP until glucose or creatine is available. Under these conditions, the membrane potential, ∆ψ, is maintained at a lower than maximal level (i.e., mild depolarization of mitochondria). This ∆ψ decrease is sufficient to completely inhibit mROS generation. In 2.5-y-old mice, mild depolarization disappears in the skeletal muscles, diaphragm, heart, spleen, and brain and partially in the lung and kidney. This age-dependent decrease in the levels of bound kinases is not observed in NMRs and bats for many years. As a result, ROS-mediated protein damage, which is substantial during the aging of short-lived mice, is stabilized at low levels during the aging of long-lived NMRs and bats. It is suggested that this mitochondrial mild depolarization is a crucial component of the mitochondrial anti-aging system

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

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. © 2018 Human Stem Cell Institute. All rights reserved

ИССЛЕДОВАНИЕ МЕХАНИЗМОВ ТЕРАПЕВТИЧЕСКОЙ АКТИВНОСТИ АЛЛОГЕННЫХ МУЛЬТИПОТЕНТНЫХ МЕЗЕНХИМАЛЬНЫХ СТРОМАЛЬНЫХ КЛЕТОК ПУПОЧНОГО КАНАТИКА В МОДЕЛИ ИШЕМИИ ЗАДНИХ КОНЕЧНОСТЕЙ КРЫС

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. © 2018 Human Stem Cell Institute. All rights reserved.Мультипотентные мезенхимальные стромальные клетки (ММСК) пупочного канатика (ПК) считаются одним из оптимальных агентов для клеточной терапии ишемии нижних конечностей. Устойчивую ишемию конечностей, сопровождающуюся асептическим воспалением, моделировали на крысах Sprague-Dawley путем иссечения бедренной и подколенной артерий. Аллогенные ММСК пупочного канатика вводили в мышцы голени на 7 сут. после повреждения. Животных выводили из эксперимента на 3, 10 или 30 сут. после трансплантации. У крыс с трансплантированными ММСК функциональное состояние мышц, определяемое тестом rota-rod, было лучше, а область повреждения мышечной ткани была значимо меньше, чем в контроле. Введение ММСК стимулировало ангиогенез в области повреждения на 1 0 сут. после трансплантации. Трансплантированные меченые клетки выживали в течение 30 сут. после введения, мигрировали в область повреждения, где частично элиминировались макрофагами реципиента и не дифференцировались в эндотелиальные и гладкомышечные клетки кровеносных сосудов. Введение ММСК ПК подавляло CD68+ макрофагальную инфильтрацию и стимулировало активацию CD206+ макрофагов в течение 10 сут. после трансплантации. Аллогенная однократная внутримышечная трансплантация ММСК ПК при ишемии задних конечностей крыс способствовала функциональному и морфологическому восстановлению ишемизированной скелетной мышечной ткани. ММСК ПК не дифференцировались в эндотелиальном направлении и не встраивались в стенки кровеносных сосудов, но стимулировали активацию прорегенераторных М2 макрофагов в области ишемического повреждения