Miro 1 Knockdown in Stem Cells Inhibits Mitochondrial Donation Mediated Rescue of Bronchial Epithelial Injury

Abstract

There is emerging evidence that stem cells can rejuvenate damaged cells by mitochondrial transfer. Here we show that Miro1, a calcium sensor that regulates mitochondrial movement in neurons, mediates mitochondrial transfer by mesenchymal stem cells (MSC) and determines their repair potential. MSC overexpressing Miro1 (MSC-Miro-Hi) show enhanced mitochondrial transfer and rescue of stressed epithelial cells, while MSC lacking Miro1 (MSC-Miro-Lo) were ineffective. Other Miro1 expressing mesenchymal-origin cells like fibroblasts could also donate mitochondria to stressed epithelial cells, with low levels of Miro1. The therapeutic relevance was tested in mouse models of rotenone induced airway injury and asthma, which has earlier been associated with epithelial mitochondrial dysfunction. Miro1 levels and mitochondrial-donor capacity of MSC were directly related to attenuation of apoptosis, airway hyperresponsiveness and remodeling. In both models, treatment with MSC-Miro-Hi was associated with better outcomes, and MSC-Miro-Lo with worse outcomes, compared to control MSC. In summary, our work provides new understanding regarding how mitochondrial transfer from stem cells happens, shows that other mesenchymal origin cells may share this property, provides definitive evidence that mitochondrial transfer is essential for stem cell mediated rescue in mouse models of asthma and airway injury, and most importantly enables strategies for increasing the repair potential of stem cells.