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Frontiers in veterinary science2022; 9; 957153; doi: 10.3389/fvets.2022.957153

The immunomodulation-immunogenicity balance of equine Mesenchymal Stem Cells (MSCs) is differentially affected by the immune cell response depending on inflammatory licensing and major histocompatibility complex (MHC) compatibility.

Abstract: The immunomodulatory properties of equine mesenchymal stem cells (MSCs) are important for their therapeutic potential and for their facilitating role in their escape from immune recognition, which may also be influenced by donor-recipient major histocompatibility complex (MHC) matching/mismatching and MHC expression level. Factors such as inflammation can modify the balance between regulatory and immunogenic profiles of equine MSCs, but little is known about how the exposure to the immune system can affect these properties in equine MSCs. In this study, we analyzed the gene expression and secretion of molecules related to the immunomodulation and immunogenicity of equine MSCs, either non-manipulated (MSC-naive) or stimulated by pro-inflammatory cytokines (MSC-primed), before and after their exposure to autologous or allogeneic MHC-matched/-mismatched lymphocytes, either activated or resting. Cytokine priming induced the immunomodulatory profile of MSCs at the baseline (MSCs cultured alone), and the exposure to activated lymphocytes further increased the expression of , and , and IL6 secretion. Activated lymphocytes were also able to upregulate the regulatory profile of MSC-naive to levels comparable to cytokine priming. On the contrary, resting lymphocytes did not upregulate the immunomodulatory profile of equine MSCs, but interestingly, MSC-primed exposed to MHC-mismatched lymphocytes showed the highest expression and secretion of these mediators, which may be potentially linked to the activation of lymphocytes upon recognition of foreign MHC molecules. Cytokine priming alone did not upregulate the immunogenic genes, but MSC-primed exposed to activated or resting lymphocytes increased their and expression, regardless of the MHC-compatibility. The upregulation of immunogenic markers including in the MHC-mismatched co-culture might have activated lymphocytes, which, at the same time, could have promoted the immune regulatory profile aforementioned. In conclusion, activated lymphocytes are able to induce the equine MSC regulatory profile, and their effects seem to be additive to the priming action. Importantly, our results suggest that the lymphocyte response against MHC-mismatched MSC-primed would promote further activation of their immunomodulatory ability, which eventually might help them evade this reaction. Further studies are needed to clarify how these findings might have clinical implications , which will help developing safer and more effective therapies.
Copyright © 2022 Cequier, Vázquez, Romero, Vitoria, Bernad, García-Martínez, Gascón, Barrachina and Rodellar.
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Publication Date: 2022-10-20 PubMed ID: 36337202PubMed Central: PMC9632425DOI: 10.3389/fvets.2022.957153Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research examines how the immune system response impacts the regulatory and immunogenic properties of horse-derived mesenchymal stem cells (MSCs). It investigates how aspects like inflammation, the presence of pro-inflammatory cytokines and types of major histocompatibility complex (MHC) matching affect these properties.

Immunomodulation and Immunogenicity of MSCs

The researchers analyzed gene expression and secretion of molecules related to immunomodulation and immunogenicity in two types of equine MSCs:

  • The MSCs that had not been manipulated (designated as MSC-naive)
  • The MSCs that had been stimulated by pro-inflammatory cytokines (referred to as MSC-primed)

Before and after their exposure to either autologous (from the same individual) or allogeneic (from a different individual) MHC-matched or MHC-mismatched lymphocytes, these cells were further categorized depending on whether they were activated or resting.

Result of Cytokine Priming

Cytokine priming instigated an immunomodulatory profile in the MSCs. This induced profile was more prominent when the cells were cultured alone. Moreover, exposure to activated lymphocytes increased the expression of immunomodulatory molecules, along with IL6 secretion.

Impact of Lymphocytes on MSCs

  • Activated lymphocytes escalated the regulatory profile of MSC-naive cells, taking them to a level equivalent to cytokine priming.
  • Resting lymphocytes did not augment the immunomodulatory profile of MSCs. However, MSC-primed cells exposed to MHC-mismatched lymphocytes showed a significant increase in the expression and secretion of these cells, which could potentially trigger the activation of lymphocytes on recognizing foreign MHC molecules.

Altered Immunogenicity in MSC-Priming

While cytokine priming alone did not augment immunogenic genes, MSC-primed cells exposed to both activated and resting lymphocytes boosted their immunogenic gene expression, irrespective of MHC-compatibility. Notably, in MHC-mismatched co-culture, the increase in immunogenic markers potentially activated lymphocytes, thereby promoting a regulatory profile.

Findings and Future Research

The crux of the research indicates that activated lymphocytes stimulate the regulatory profile in equine MSCs. This effect is compounded by the action of cytokine priming. More importantly, the researchers shed light on the possibility of further activation of the immunomodulatory ability in MHC-mismatched MSC-primed cells when subjected to a lymphocyte response, which may aid them in evading such reactions. Further studies are essential to clarify the clinical implications of these findings for the development of superior and safer therapeutic interventions.

Cite This Article

APA
Cequier A, Vázquez FJ, Romero A, Vitoria A, Bernad E, García-Martínez M, Gascón I, Barrachina L, Rodellar C. (2022). The immunomodulation-immunogenicity balance of equine Mesenchymal Stem Cells (MSCs) is differentially affected by the immune cell response depending on inflammatory licensing and major histocompatibility complex (MHC) compatibility. Front Vet Sci, 9, 957153. https://doi.org/10.3389/fvets.2022.957153

Publication

Frontiers in veterinary science
ISSN: 2297-1769
NlmUniqueID: 101666658
Country: Switzerland
Language: English
Volume: 9
Pages: 957153
PII: 957153

Researcher Affiliations

Cequier, Alina
  • Laboratorio de Genética Bioquímica LAGENBIO, Instituto de Investigación Sanitaria de Aragón (IIS), Instituto Agroalimentario de Aragón-IA2 (Universidad de Zaragoza-CITA), Zaragoza, Spain.
  • Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, Zaragoza, Spain.
Vázquez, Francisco José
  • Laboratorio de Genética Bioquímica LAGENBIO, Instituto de Investigación Sanitaria de Aragón (IIS), Instituto Agroalimentario de Aragón-IA2 (Universidad de Zaragoza-CITA), Zaragoza, Spain.
  • Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, Zaragoza, Spain.
Romero, Antonio
  • Laboratorio de Genética Bioquímica LAGENBIO, Instituto de Investigación Sanitaria de Aragón (IIS), Instituto Agroalimentario de Aragón-IA2 (Universidad de Zaragoza-CITA), Zaragoza, Spain.
  • Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, Zaragoza, Spain.
Vitoria, Arantza
  • Laboratorio de Genética Bioquímica LAGENBIO, Instituto de Investigación Sanitaria de Aragón (IIS), Instituto Agroalimentario de Aragón-IA2 (Universidad de Zaragoza-CITA), Zaragoza, Spain.
  • Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, Zaragoza, Spain.
Bernad, Elvira
  • Laboratorio de Genética Bioquímica LAGENBIO, Instituto de Investigación Sanitaria de Aragón (IIS), Instituto Agroalimentario de Aragón-IA2 (Universidad de Zaragoza-CITA), Zaragoza, Spain.
García-Martínez, Mirta
  • Laboratorio de Genética Bioquímica LAGENBIO, Instituto de Investigación Sanitaria de Aragón (IIS), Instituto Agroalimentario de Aragón-IA2 (Universidad de Zaragoza-CITA), Zaragoza, Spain.
Gascón, Isabel
  • Laboratorio de Genética Bioquímica LAGENBIO, Instituto de Investigación Sanitaria de Aragón (IIS), Instituto Agroalimentario de Aragón-IA2 (Universidad de Zaragoza-CITA), Zaragoza, Spain.
Barrachina, Laura
  • Laboratorio de Genética Bioquímica LAGENBIO, Instituto de Investigación Sanitaria de Aragón (IIS), Instituto Agroalimentario de Aragón-IA2 (Universidad de Zaragoza-CITA), Zaragoza, Spain.
  • Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, Zaragoza, Spain.
Rodellar, Clementina
  • Laboratorio de Genética Bioquímica LAGENBIO, Instituto de Investigación Sanitaria de Aragón (IIS), Instituto Agroalimentario de Aragón-IA2 (Universidad de Zaragoza-CITA), Zaragoza, Spain.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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