Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy

Abstract

There is emerging evidence that stem cells can rejuvenate damaged cells by mitochondrial transfer. Earlier studies show that epithelial mitochondrial dysfunction is critical in asthma pathogenesis. Here we show for the first time that Miro1, a mitochondrial Rho-GTPase, regulates intercellular mitochondrial movement from mesenchymal stem cells (MSC) to epithelial cells (EC). We demonstrate that overexpression of Miro1 in MSC (MSCmiro(Hi)) leads to enhanced mitochondrial transfer and rescue of epithelial injury, while Miro1 knockdown (MSCmiro(Lo)) leads to loss of efficacy. Treatment with MSCmiro(Hi) was associated with greater therapeutic efficacy, when compared to control MSC, in mouse models of rotenone (Rot) induced airway injury and allergic airway inflammation (AAI). Notably, airway hyperresponsiveness and remodeling were reversed by MSCmiro(Hi) in three separate allergen-induced asthma models. In a human in vitro system, MSCmiro(Hi) reversed mitochondrial dysfunction in bronchial epithelial cells treated with pro-inflammatory supernatant of IL-13-induced macrophages. Anti-inflammatory MSC products like NO, TGF-β, IL-10 and PGE2, were unchanged by Miro1 overexpression, excluding non-specific paracrine effects. In summary, Miro1 overexpression leads to increased stem cell repair.

Improving the Post-Stroke Therapeutic Potency of Mesenchymal Multipotent Stromal Cells by Cocultivation With Cortical Neurons: The Role of Crosstalk Between Cells

“…This emphasizes the significance of our findings on the induced elevation in MMSCs of Miro1, which is responsible for mitochondrial transport. Earlier it was demonstrated that a genetically induced increase of Miro1 in MMSCs results in greater therapeutic efficiency of MMSCs [24]. Accordingly, a higher level of Miro1 can be reached, not only by introduction of a genetic construct, but also by a cocultivation procedure.…”

“…In addition, the amount of important intracellular factor associated with mitochondria transport, specifically, Rho GTPase Miro1, was evaluated. This ubiquitous GTPase is known to be responsible for intercellular traffic of mitochondria [24]. The level of this protein was detectible in native MMSCs but was more than doubled in MMSCs exposed to the cocultivation procedure with neural cells (Fig.…”

Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy

“…Recent studies analyzing mitochondria exchange in other cellular systems identified some molecular players such as the gap junction protein connexin 43 10 or the mitochondrial r-GTPase Miro1. 25 We show in our model that mitochondrial uptake could undergo through endocytosis machinery in a process that remains to be better defined at a molecular level. In subconfluent cultures, we observed that MS-5 cells produce many vincristinesensitive membrane protrusions a feature of their ability to search and find other cellular partners that could be the basis of mitochondria transfer.…”

Mesenchymal stem cells: mechanisms of potential therapeutic benefit in ARDS and sepsis

“…Ahmad et al 74 In-vitro and in-vivo evidence of mitochondrial transfer between MSCs and injured epithelial cells via nanotubes which rescues epithelial cells from infl ammation and improves host bioenergetics Li et al 75 Mitochondrial transfer between human MSCs derived from induced pluripotent stem cells and lung epithelial cells injured by cigarette smoke both in vitro and in an in-vivo rat model…”