Mitochondrial transplantation attenuates hypoxic pulmonary hypertension

Abstract

Mitochondria are essential for the onset of hypoxia-induced pulmonary vasoconstriction and pulmonary vascular-remodeling, two major aspects underlying the development of pulmonary hypertension, an incurable disease. However, hypoxia induces relaxation of systemic arteries such as femoral arteries and mitochondrial heterogeneity controls the distinct responses of pulmonary versus femoral artery smooth muscle cells to hypoxia in vitro. The aim of this study was to determine whether mitochondrial heterogeneity can be experimentally exploited in vivo for a potential treatment against pulmonary hypertension. The intact mitochondria were transplanted into Sprague-Dawley rat pulmonary artery smooth muscle cells in vivo via intravenous administration. The immune-florescent staining and ultrastructural examinations on pulmonary arteries confirmed the intracellular distribution of exogenous mitochondria and revealed the possible mitochondrial transfer from pulmonary artery endothelial cells into smooth muscle cells in part through their intercellular space and intercellular junctions. The transplantation of mitochondria derived from femoral artery smooth muscle cells inhibited acute hypoxia-triggered pulmonary vasoconstriction, attenuated chronic hypoxia-induced pulmonary vascular remodeling, and thus prevented the development of pulmonary hypertension or cured the established pulmonary hypertension in rats exposed to chronic hypoxia. Our findings suggest that mitochondrial transplantation possesses potential implications for exploring a novel therapeutic and preventive strategy against pulmonary hypertension.

Mitochondria transfer from mesenchymal stem cells structurally and functionally repairs renal proximal tubular epithelial cells in diabetic nephropathy in vivo

“…Mt isolated from BM-MSCs were incorporated into injured renal tubules in vivo 1 d after the administration of Mt, whereby they induced histological improvements of proximal tubules in STZ rats within 3 d. According to previous reports, most of the intravenously administered Mt were trapped in the lungs and did not distribute to the kidneys 53 . From this result, we considered that it is difficult to assess the effect of MSC-derived isolated Mt on kidneys by systematic intravenous administration.…”

Mitochondria Donation by Mesenchymal Stem Cells: Current Understanding and Mitochondria Transplantation Strategies

“…Mitochondrial transplantation strategies based on the systemic injection of isolated functional mitochondria, stem cells, or EVs still do not possess a specificity of delivery and will affect a variety of cells, such as blood cells and vessel-rich organs such as the lung and liver. Previously, it was shown that the intravenous administration of isolated mitochondria caused the mitochondria to become trapped in the lungs ( Zhu et al, 2016 ), while the therapeutic efficacy of mitochondrial transplantation for the treatment of tissue injury or mitochondria-associated disorders will benefit from the targeted delivery of mitochondria into a specific tissue or organs. Due to the inherited characteristics of mitochondrial diseases and the presence of defective mitochondria in every cell of an organism, specificity of mitochondrial delivery is not always strictly necessary.…”

COMP-prohibitin 2 interaction maintains mitochondrial homeostasis and controls smooth muscle cell identity

“…To further investigate whether mitochondrial or non-mitochondrial COMP is responsible for VSMC identity, we performed mitochondrial transplantation as described previously 33 , 34 . The mitochondria were isolated from scrambled or COMP- silenced donor VSMCs and then transplanted into recipient mitochondria-deleted VSMCs treated with scrambled or COMP siRNA respectively (Fig.…”

“…Mitochondria were transplanted as previously described 33 , 34 . To remove endogenous mitochondria, VSMCs at 80% confluence in culture were either maintained in DMEM as control or treated in DMEM supplemented with 110 µg/ml sodium pyruvate, 50 µg/ml uridine, and different concentrations of ethidium bromide (50, 100, or 200 ng/ml), respectively.…”