Review Article | Published:

Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases

Nature Reviews Nephrology (2018) | Download Citation

Abstract

Mesenchymal stem cells (MSCs; also referred to as mesenchymal stromal cells) have attracted much attention for their ability to regulate inflammatory processes. Their therapeutic potential is currently being investigated in various degenerative and inflammatory disorders such as Crohn’s disease, graft-versus-host disease, diabetic nephropathy and organ fibrosis. The mechanisms by which MSCs exert their therapeutic effects are multifaceted, but in general, these cells are thought to enable damaged tissues to form a balanced inflammatory and regenerative microenvironment in the presence of vigorous inflammation. Studies over the past few years have demonstrated that when exposed to an inflammatory environment, MSCs can orchestrate local and systemic innate and adaptive immune responses through the release of various mediators, including immunosuppressive molecules, growth factors, exosomes, chemokines, complement components and various metabolites. Interestingly, even nonviable MSCs can exert beneficial effects, with apoptotic MSCs showing immunosuppressive functions in vivo. Because the immunomodulatory capabilities of MSCs are not constitutive but rather are licensed by inflammatory cytokines, the net outcomes of MSC activation might vary depending on the levels and the types of inflammation within the residing tissues. Here, we review current understanding of the immunomodulatory mechanisms of MSCs and the issues related to their therapeutic applications.

Key points

  • Mesenchymal stem cells (MSCs; also known as mesenchymal stromal cells) actively contribute to the microenvironment of injured tissues, where they promote tissue regeneration by cell replacement, by empowering the regenerative capacity of in situ cells and through immunomodulatory mechanisms.

  • The plasticity of immunoregulation by MSCs is controlled by the intensity and complexity of inflammatory stimuli.

  • Multiple factors, including immunosuppressive factors, growth factors, exosomes, chemokines and apoptotic cells, contribute to the immunosuppressive mechanisms of MSCs.

  • Given the plasticity of the immunoregulatory phenotype of MSCs, inflammatory status and concurrent use of immunosuppressants should be considered when administering MSCs for the treatment of inflammatory diseases.

  • Greater understanding of the mechanisms that control the plasticity of MSC immunoregulation will lead to the development of novel therapeutic strategies.

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ClinicalTrials.gov: https://clinicaltrials.gov

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Acknowledgements

The authors apologize to those whose work is not discussed here owing to space limitations. The authors’ work described in this Review is supported by grants from the National Key R&D Program of China (2018YFA0107500), the Scientific Innovation Project of the Chinese Academy of Sciences (XDA16020403), the Ministry of Science and Technology of China (2015CB964400), the National Natural Science Foundation of China (81530043, 81330046, 81861138015, 31771641 and 81571612), the Youth Innovation Promotion Association research fund from the Chinese Academy of Sciences, a start-up fund from Soochow University and the Department of Science and Technology of Jiangsu Province research fund (BE2016671).

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Affiliations

  1. The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, China

    • Yufang Shi
    • , Jianquan Hou
    •  & Changshun Shao
  2. CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences/Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    • Yufang Shi
    • , Yu Wang
    • , Qing Li
    • , Keli Liu
    •  & Ying Wang

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Contributions

All authors contributed to discussion of the outline and the content of the article, wrote the article and reviewed and edited the manuscript before submission. Y.S., Yu.W., Q.L., K.L., C.S. and Yi.W. created the figure drafts, and Yu.W., Q.L. and K.L. prepared the tables.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Yufang Shi or Ying Wang.

Glossary

Colonies

Cell communities in which all of the daughter cells are derived from one ancestor cell.

Mechanical memory

A phenomenon whereby cells can be permanently imprinted by exposure to certain mechanical conditions.

Perforin

A pore-forming cytolytic protein expressed in cytotoxic T cells and NK cells. It aids the delivery of granzymes to target cells to induce cell death.

Efferocytosis

The process by which phagocytic cells remove dead cells.

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