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Mesenchymal Stem Cell—Macrophage Crosstalk Provides Specific Exosomal Cargo to Direct Immune Response Licensing of Macrophages during Inflammatory Responses

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Abstract

Neurodegenerative diseases (NDDs) continue to be a significant healthcare problem. The economic and social implications of NDDs increase with longevity. NDDs are linked to neuroinflammation and activated microglia and astrocytes play a central role. There is a growing interest for stem cell-based therapy to deliver genes, and for tissue regeneration. The promise of mesenchymal stem cells (MSC) is based on their availability as off-the-shelf source, and ease of expanding from discarded tissues. We tested the hypothesis that MSC have a major role of resetting activated microglial cells. We modeled microglial cell lines by using U937 cell-derived M1 and M2 macrophages. We studied macrophage types, alone, or in a non-contact culture with MSCs. MSCs induced significant release of exosomes from both types of macrophages, but significantly more of the M1 type. RNA sequencing showed enhanced gene expression within the exosomes with the major changes linked to the inflammatory response, including cytokines and the purinergic receptors. Computational analyses of the transcripts supported the expected effect of MSCs in suppressing the inflammatory response of M1 macrophages. The inflammatory cargo of M1 macrophage-derived exosomes revealed involvement of cytokines and purinergic receptors. At the same time, the exosomes from MSC-M2 macrophages were able to reset the classical M2 macrophages to more balanced inflammation. Interestingly, we excluded transfer of purinergic receptor transcripts from the co-cultured MSCs by analyzing these cells for the identified purinergic receptors. Since exosomes are intercellular communicators, these findings provide insights into how MSCs may modulate tissue regeneration and neuroinflammation.

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Acknowledgements

HU acknowledges grant support for his work on purinergic signaling by the São Paulo Research Foundation [(FAPESP) Project No. 2018/07366-4 and 2012/50880-4] and the National Institute of Science and Technology in Regenerative Medicine (INCT-REGENERA), Brazil, as well as by the National Council of Scientific and Technological Development (CNPq Project No. 406396/2021 and 308012/2021-6). YN was supported by FAPESP fellowship (Project No. 2017/23604-0 and 2015/14343-2) and NT acknowledges a doctoral fellowship from FAPESP (Project No 2020/10725-6). H.U. was awarded with a Fulbright Chair in Global Health Brazil at Rutgers New Jersey Medical School.

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Authors and Affiliations

  1. Department of Medicine, Rutgers New Jersey Medical School (NJMS), Newark, NJ, USA

    Yahaira Naaldijk, Lauren S. Sherman & Pranela Rameshwar

  2. Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, 05508-000, Brazil

    Yahaira Naaldijk, Natalia Turrini & Henning Ulrich

  3. Rutgers School of Graduate Studies at NHMS, Newark, NJ, USA

    Lauren S. Sherman & Yannick Kenfack

  4. Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA

    Mariusz Z. Ratajczak

  5. Laboratory of Regenerative Medicine at Medical University of Warsaw, Warsaw, Poland

    Mariusz Z. Ratajczak

  6. Department of Neurology, Rutgers New Jersey Medical School, Newark, NJ, USA

    Nizar Souayah

  7. Department of Neuroscience and Physiology, Rutgers New Jersey Medical School, Newark, NJ, USA

    Henning Ulrich

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  1. Yahaira Naaldijk
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  2. Lauren S. Sherman
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YN conducted the experiments, analyzed the data, provided the concepts, and prepare the first draft of the manuscript. LSS cultured MSCs, conducted experiments, wrote the manuscript, and analyzed the data. NT wrote the manuscript and performed data analyses. YK wrote the manuscript and performed data analyses. MZR provided intellectual input into the overall design, edited the paper and analyzed the data. NS provided reagents, edited the manuscript, and provided intellectual input. PR wrote and edited the final version of the manuscript and is responsible for the ethics of using human bone marrow aspirates, and provided the concepts for the experimental design. HU wrote and edited the final version of the manuscript and provided the conceptualized overall hypothesis.

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Correspondence to Pranela Rameshwar or Henning Ulrich.

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Naaldijk, Y., Sherman, L.S., Turrini, N. et al. Mesenchymal Stem Cell—Macrophage Crosstalk Provides Specific Exosomal Cargo to Direct Immune Response Licensing of Macrophages during Inflammatory Responses. Stem Cell Rev and Rep 20, 218–236 (2024). https://doi.org/10.1007/s12015-023-10612-3

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