Editors' ChoiceCell-Based Therapy

Brother, Can You Spare Some Mitochondria?

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Science Translational Medicine  02 May 2012:
Vol. 4, Issue 132, pp. 132ec78
DOI: 10.1126/scitranslmed.3004206

Acute lung injury is a common form of respiratory failure in critically ill patients, with 30 to 40% associated mortality and no effective treatments other than supportive care. Mesenchymal stem cells, also known as bone marrow–derived stromal cells (BMSCs), improve survival in mouse models of acute lung injury and will likely soon be in clinical trials for this indication. Some prior studies have demonstrated that the conditioned culture media from mesenchymal stem cells is nearly as potent as the cells themselves, raising the question of whether cell-cell contact is required for the BMSCs to be effective. The recent publication by Islam et al. on mitochondrial transfer from BMSCs to injured lung epithelial cells provides new and important insight into this question.

Using intravital microscopy in a mouse model of lipopolysaccharide (LPS)–induced lung injury, Islam and colleagues first demonstrated that mouse BMSCs administered intratracheally attach to alveolar epithelial cells after injury via gap junctional channels. Once attached, the BMSCs then release mitochondria-containing microvesicles, which then seem to be engulfed by the epithelium. The presence of the BMSC-derived mitochondria within the epithelium was demonstrated both with clear intravital microscopic imaging, as well as by the presence of human mitochondrial DNA in alveolar epithelial cells from mouse lungs that had been treated with human BMSCs. Last, the authors confirmed prior reports that mouse BMSCs reduced the severity of LPS-induced acute lung injury and also enhanced survival. They also demonstrated that mutant mouse BMSCs lacking the ability to form gap junction channels or transfected with dysfunctional mitochondria were not similarly protective. These impressive results have strong biologic plausibility, because abnormal lung mitochondrial energetics are thought to contribute to the pathophysiology of organ failure in critical illness.

Several unanswered questions remain, including the relative importance of cell-contact dependent versus independent mechanisms in the therapeutic effect of BMSCs in this setting, and perhaps most importantly, what the role of mitochondrial transfer is in other clinical settings in which BMSCs are being tested (including myocardial infarction, inflammatory bowel disease, and graft-versus-host disease). Also, the exact mechanism for the transfer of mitochondria will need further study. Nevertheless, these new data from Islam et al. have important implications for the growing field of cell-based therapies, suggesting that the cells themselves, and not just their media, may be required for an optimal therapeutic effect.

M. N. Islam et al., Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat. Med. 15 April 2012 (10.1038/nm.2736). [Abstract]

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