You are here

| Mesenchymal Stem Cells

iPSC-MSC in vivo Study Uncovers Novel Immunomodulatory Mechanism

Comment

Discuss

Review of “Human iPSC-MSC-Derived Xenografts Modulate Immune Responses by Inhibiting the Cleavage of Caspases” from STEM CELLS by Stuart P. Atkinson

The robust immunomodulatory capabilities of mesenchymal stem cells (MSCs) have propelled them into animal studies and preliminary clinical trials as a treatment for a series of immunological diseases. The differentiation of MSCs from induced pluripotent stem cells (iPSCs) may allow for the generation of vast numbers of patient-matched cells that display high similarities to bone marrow MSCs (BM-MSCs) [1, 2].

Now, a new STEM CELLS study from the labs of Qing-Ling Fu (Sun Yat-sen University, Guangzhou) and Zhongquan Qi (Xiamen University, Fujian, PR China) has described the effect of iPSC-MSCs on immune T cells in a relevant in vivo mouse model. This new study suggests that iPSC-MSC-secreted factors modulate T cell responses by inhibiting the cleavage of caspases, in what represents a novel immunomodulatory mechanism [3].

To assess the immunomodulatory role of iPSC-MSCs in vivo, Li et al. studied the immune response elicited following human vascular endothelial cell (HUVEC) subcapsular kidney grafting in immunocompetent C57BL/6 mice [4]. While HUVECs raised a significant immune response when grafted alone, iPSC-MSC co-administration enhanced HUVEC survival (See Figure) and altered T cell responses to promote anti-inflammatory conditions via the secretion of high levels of immunomodulatory factors (TGF-β1/2/3, IL-10, and MCP-1).

 

Interestingly, administration of iPSC-MSCs (or a combination of the soluble immunomodulatory factors noted above) also decreased the levels of activated (cleaved) caspase proteins (3 and 8) in T cells, and so the data suggested that caspase inhibition might represent a novel immunomodulatory mechanism. Indeed, the authors also observed that the downregulation of caspase activity via the application of specific inhibitors also promoted anti-inflammatory responses.

The new immunomodulatory mechanism uncovered employing an in vivo mouse model suggests that iPSC-MSCs secreted immunomodulatory factors inhibit the cleavage of caspases and suppress T cell responses to promote an anti-inflammatory environment. Furthermore, this study also encourages the application of iPSC-MSCs as an exciting new therapeutic option for a range of immunological disorders and suggests that further study of the secreted factors may allow the construction of efficient cell-free therapies in the near future.

To keep up to date with the immunomodulatory properties of iPSC-MSCs, stay tuned to the Stem Cells Portal!

Discussion Points

  • What is the mechanistic link between immunomodulatory factor expression and inhibition of caspase cleavage and further anti-inflammatory responses?
  • What other iPSC-MSC-secreted factors are involved?
  • How long do iPSC-MSCs survive in vivo and are they safe in the long term?
  • Will other iPSC-derived stem and progenitor cells display elevated therapeutic potential?

References

  1. Lian Q, Zhang Y, Zhang J, et al. Functional mesenchymal stem cells derived from human induced pluripotent stem cells attenuate limb ischemia in mice. Circulation 2010;121:1113-1123.
  2. Frobel J, Hemeda H, Lenz M, et al. Epigenetic rejuvenation of mesenchymal stromal cells derived from induced pluripotent stem cells. Stem Cell Reports 2014;3:414-422.
  3. Li C-L, Leng Y, Zhao B, et al. Human iPSC-MSC-Derived Xenografts Modulate Immune Responses by Inhibiting the Cleavage of Caspases. STEM CELLS 2017;35:1719-1732.
  4. Imaizumi T, Kumagai M, Sasaki N, et al. Interferon-gamma stimulates the expression of galectin-9 in cultured human endothelial cells. J Leukoc Biol 2002;72:486-491.