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Describing the Anti-microbial Effect of MSCs in ARDS

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Review of “Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the in vitro and in vivo Models of ARDS” from Stem Cells by Stuart P. Atkinson

Studies show that mesenchymal stem cells (MSCs) transplantation is beneficial for the treatment of Acute Respiratory Distress Syndrome (ARDS) [1], a disorder most often brought on by bacterial and viral pneumonia and sepsis in the lungs. This has led to MSC application in clinical trials [2, 3] with successful recovery reported in two patients after MSC administration on a compassionate basis [4].

Researchers from the laboratory of Anna Krasnodembskaya (Queen's University of Belfast, UK) aimed to discover the mechanisms behind the anti-microbial effect of MSCs in ARDS, with a focus on the potential for MSC modulation of alveolar macrophage (AM) phagocytic activity via mitochondrial transfer. In a new Stem Cells study, they now report that MSC transfer mitochondria to macrophages via tunneling nanotubes (TNT) leading to enhanced macrophage function and improved bioenergetics [5].

Using selective depletion of AMs employing intranasal administration of clodronate liposomes in a mouse model of Escherichia coli pneumonia, the authors first demonstrated the absolute requirement for AMs in the antimicrobial effect of MSCs. In fact, the authors established that MSCs increased the phagocytic activity of AMs against bacteria, and they also extended this to humans, where in vitro analyses suggested that MSCs also boosted the phagocytic function of human monocyte-derived macrophages (MDMs).

So what is the special relationship between these cell types? Multiple studies have previously established that mitochondrial transfer represents an important mechanism behind MSC protective effects, and so they assessed this hypothesis employing MSCs labeled with a mitochondrial tracking stain. This demonstrated that MDMs took up MSC mitochondria in vitro and in vivo via the formation of tunneling nanotubes (TNT) and that this transfer enhanced phagocytic activity via an increase in mitochondrial function and ATP turnover. The attached figure shows the colocalization of human MDMs (blue) and MSC mitochondria (red) and a network of mitochondria-positive TNT connecting MSC and macrophages (arrows).

This exciting study describes, for the first time, the anti-microbial effect of MSCs in ARDS. Direct transfer of mitochondria to phagocytes via TNTs proved to boost phagocytosis and improve bioenergetics, and overall, this improves our understanding of the therapeutic benefits of MSCs transplantation. The authors hope to build on this study and go on to discover just how MSC mitochondria facilitate macrophage phagocytosis and the effects of transfer on other macrophage functions. This sounds like the start of a long and interesting story!

References

  1. Force ADT, Ranieri VM, Rubenfeld GD, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA 2012;307:2526-2533.
  2. Wilson JG, Liu KD, Zhuo H, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med 2015;3:24-32.
  3. Zheng G, Huang L, Tong H, et al. Treatment of acute respiratory distress syndrome with allogeneic adipose-derived mesenchymal stem cells: a randomized, placebo-controlled pilot study. Respir Res 2014;15:39.
  4. Simonson OE, Mougiakakos D, Heldring N, et al. In Vivo Effects of Mesenchymal Stromal Cells in Two Patients With Severe Acute Respiratory Distress Syndrome. Stem Cells Transl Med 2015;4:1199-1213.
  5. Jackson MV, Morrison TJ, Doherty DF, et al. Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS. STEM CELLS 2016;34:2210-2223.