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Open Access

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

Tanveer Ahmad, Shravani Mukherjee, Bijay Pattnaik, Manish Kumar, Suchita Singh, Manish Kumar, Rakhshinda Rehman, Brijendra K Tiwari, Kumar A Jha, Amruta P Barhanpurkar, Mohan R Wani, Soumya S Roy, Ulaganathan Mabalirajan, Balaram Ghosh, Anurag Agrawal

Author Affiliations

  1. Tanveer Ahmad1,,
  2. Shravani Mukherjee1,,
  3. Bijay Pattnaik1,
  4. Manish Kumar1,
  5. Suchita Singh1,
  6. Manish Kumar2,
  7. Rakhshinda Rehman1,
  8. Brijendra K Tiwari3,
  9. Kumar A Jha4,
  10. Amruta P Barhanpurkar5,
  11. Mohan R Wani5,
  12. Soumya S Roy1,
  13. Ulaganathan Mabalirajan1,
  14. Balaram Ghosh1 and
  15. Anurag Agrawal*,1
  1. 1Centre of Excellence in Asthma & Lung Disease, CSIR‐Institute of Genomics and Integrative Biology, Delhi, India
  2. 2Central Instrumentation Facility, Biotech Centre University of Delhi South Campus, Delhi, India
  3. 3Department of Allergy and Infectious Diseases, CSIR‐Institute of Genomics and Integrative Biology, Delhi, India
  4. 4Department of Anatomy, All India Institute of Medical Sciences, Delhi, India
  5. 5Department of Cell Biology, National Centre for Cell Science Pune University Campus, Pune, India
  1. *Corresponding author. Tel: 011 27662075; Fax: 011 27667471; E‐mail: a.agrawal{at}igib.res.in
  1. These authors contributed equally to this work.

  2. Author contributions

    The author(s) have made the following declarations about their contributions: TA and SM wrote the paper; conceived, designed and performed the experiments, also analysed the data; BP, MK, BKT, RR, SS, MK, AKJ performed the experiments. APB and MRW provided the human stem cells, SSR, BG and UM analysed the data and wrote the paper, also AA analysed the data, wrote the paper and provided overall scientific guidance and financial support.

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

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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.

Footnotes

  • Conflict of interest

    The authors declare that they have no conflict of interest.

  • Received June 19, 2013.
  • Revision received December 3, 2013.
  • Accepted December 5, 2013.

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