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

Authors


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 (MSCmiroHi) leads to enhanced mitochondrial transfer and rescue of epithelial injury, while Miro1 knockdown (MSCmiroLo) leads to loss of efficacy. Treatment with MSCmiroHi 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 MSCmiroHi in three separate allergen-induced asthma models. In a human in vitro system, MSCmiroHi 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.

Synopsis

image

This study presents the first mechanistic insight into how Mesenchymal Stem Cells (MSC) act as mitochondrial donors during attenuation of lung inflammation and injury. Mitochondrial donation is an essential part of the MSC therapeutic effect in these models and is positively regulated by Miro1 / Rhot1 mitochondrial transport proteins.

  • MSC can donate mitochondria to stressed epithelial cells (EC) with mitochondrial dysfunction. Cytoplasmic nanotubular bridges form between the cells and Miro-1 mediated mitochondrial transfer occurs unidirectionally from MSC to EC.
  • Other mesenchymal cells like smooth muscle cells and fibroblasts express Miro1 and can also donate mitochondria to EC, but with low efficiency. EC have very low levels of Miro1 and do not donate mitochondria.
  • Enhanced expression of Miro1 in mesenchymal cells increases their mitochondrial donor efficiency. Conversely, Miro1-knockdown inhibits MSC mediated mitochondrial donation.
  • Miro1-overexpressing MSC have enhanced therapeutic effects in three different models of allergic lung inflammation and rotenone induced lung injury. Conversely, Miro1-depleted MSC lose much of their therapeutic effect. Miro1 overexpression in MSC may lead to more effective stem cell therapy.

Ancillary