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Transfer of Processing Bodies Mediates Long-Term MSC Immunomodulation

Review of “Mesenchymal Stromal Cells Reprogram Monocytes and Macrophages with Processing Bodies” from STEM CELLS by Stuart P. Atkinson

Mesenchymal stem cell (MSC) therapy induces long-term immunomodulation; however, their rapid clearance from the body shortly after intravenous administration provides MSCs with only a brief opportunity to reprogram inflammatory responses (See an associated STEM CELLS article here!) [1]. MSCs become engulfed by monocytes and macrophages in the lungs, spleen, liver, kidneys, and lymph nodes soon after administration [1], a mechanism that induces anti-inflammatory reprogramming of these crucial immune cells [1, 2]. Of particular note, MSC therapy fails to suppress inflammation in the absence of monocytes and macrophages [3].

In a new STEM CELLS study, researchers led by Anthony J. Filiano (Duke University, Durham NC, USA) report on their exploration of the molecular pathways involved in the reprogramming of monocytes and macrophages after they engulf MSCs [4]. Excitingly, Min et al. now establish the importance of processing (p)-bodies (phase-separated cytosolic membrane-less organelles that store RNA, miRNA, and proteins [5-7]) in the reprogramming of monocytes and macrophages by MSCs and the suppression of T-cell responses.

This fascinating new study demonstrated that engulfed human umbilical cord-derived MSCs transfer cytoplasmic components to monocytes and macrophages, which mediates the significant and long-lasting downregulated expression of genes associated with antigen presentation and co-stimulation and the subsequent suppression of T cell activation at a time when MSCs were no longer present. Of note, the presence of low-density lipoprotein receptor-related proteins on monocytes and macrophages mediated the interactions between MSCs by monocytes and macrophages.

The authors then created MSCs that lacked p-bodies to explore their possible role in immune cell reprogramming, achieving this feat through the CRISPR/Cas9-mediated deletion of the DDX6 ATP-dependent RNA helicase, which is known to stabilize p‐bodies [8]. While monocytes and macrophages engulfed p-body deficient MSCs in vitro and in vivo, they failed to reprogram monocytes and macrophages, leading to an overall failure to suppress inflammation.

Overall, the authors provide evidence that the transfer of p-bodies from engulfed MSCs to immune cells can mediate the long-term suppression of T cell responses/inflammation both in vivo and in vitro in the absence of long-term MSC engraftment.

For more on how MSCs modulate the immune system and inhibit inflammation, stay tuned to the Stem Cells Portal.


References

  1. de Witte SFH, Luk F, Sierra Parraga JM, et al., Immunomodulation By Therapeutic Mesenchymal Stromal Cells (MSC) Is Triggered Through Phagocytosis of MSC By Monocytic Cells. STEM CELLS 2018;36:602-615.
  2. Galleu A, Riffo-Vasquez Y, Trento C, et al., Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. Science Translational Medicine 2017;9:eaam7828.
  3. Cutler AJ, Limbani V, Girdlestone J, et al., Umbilical Cord-Derived Mesenchymal Stromal Cells Modulate Monocyte Function to Suppress T Cell Proliferation. The Journal of Immunology 2010;185:6617.
  4. Min H, Xu L, Parrott R, et al., Mesenchymal stromal cells reprogram monocytes and macrophages with processing bodies. STEM CELLS 2021;39:115-128.
  5. Standart N and Weil D, P-Bodies: Cytosolic Droplets for Coordinated mRNA Storage. Trends in Genetics 2018;34:612-626.
  6. Oh J-Y, Kwon A, Jo A, et al., Activity-dependent synaptic localization of processing bodies and their role in dendritic structural plasticity. Journal of Cell Science 2013;126:2114.
  7. Hubstenberger A, Courel M, Bénard M, et al., P-Body Purification Reveals the Condensation of Repressed mRNA Regulons. Molecular Cell 2017;68:144-157.e5.
  8. Ayache J, Bénard M, Ernoult-Lange M, et al., P-body assembly requires DDX6 repression complexes rather than decay or Ataxin2/2L complexes. Molecular Biology of the Cell 2015;26:2579-2595.