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The Potential Role of Genetically-Modified Pig Mesenchymal Stromal Cells in Xenotransplantation

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Abstract

Mesenchymal stromal cells (MSCs) are known to have regenerative, anti-inflammatory, and immunodulatory effects. There are extensive indications that pig MSCs function satisfactorily across species barriers. Pig MSCs might have considerable therapeutic potential, particularly in xenotransplantation, where they have several potential advantages. (i) pMSCs can be obtained from the specific organ- or cell-source donor pig or from an identical (cloned) pig. (ii) They are easy to obtain in large numbers, negating the need for prolonged ex vivo expansion. (iii) They can be obtained from genetically-engineered pigs, and the genetic modification can be related to the therapeutic goal of the MSCs. We have reviewed our own studies on MSCs from genetically-engineered pigs, and summarize them here. We have successfully harvested and cultured MSCs from wild-type and genetically-engineered pig bone marrow and adipose tissue. We have identified several pig (p)MSC surface markers (positive for CD29, CD44, CD73, CD105, CD166, and negative for CD31, CD45), have demonstrated their proliferation and differentiation (into adipocytes, osteoblasts, and chondroblasts), and evaluated their antigenicity and immune suppressive effects on human peripheral blood mononuclear cells and CD4+T cells. They have identical or very similar characteristics to MSCs from other mammals. Genetically-modified pMSCs are significantly less immunogenic than wild-type pMSCs, and downregulate the human T cell response to pig antigens as efficiently as do human MSCs. We hypothesized that pMSCs can immunomodulate human T cells through induction of apoptosis or anergy, or cause T cell phenotype switching with induction of regulatory T cells, but we could find no evidence for these mechanisms. However, pMSCs upregulated the expression of CD69 on human CD4+ and CD8+ T cells, the relevance of which is currently under investigation. We conclude that MSCs from genetically-engineered pigs should continue to be investigated for their immunomodulatory (and regenerative and anti-inflammatory) effects in pig-to-nonhuman primate organ and cell transplantation models.

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Abbreviations

AdMSC:

Adipose-derived mesenchymal stromal cells

AECs:

Aortic endothelial cells

Gal:

Galactose-α1,3-galactose

GTKO:

α1,3-galactosyltransferase gene-knockout

MLR:

Mixed lymphocyte reaction

MSC:

Mesenchymal stromal cells

PBMC:

Peripheral blood mononuclear cells

SLA:

Swine leukocyte antigen

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Acknowledgments

Jiang Li is funded by the China Scholarship Council. Mohamed Ezzelarab is supported in part by the Joseph A. Patrick Research Fellowship in Transplantation of the Thomas E. Starzl Transplantation Institute of the University of Pittsburgh. Studies on xenotransplantation at the Thomas E. Starzl Transplantation Institute are supported in part by CMRF (competitive medical research funding) from the University of Pittsburgh Medical Center, NIH grants #1U19AI090959-01 and #1PO1 HL107152, and by Sponsored Research Agreements between the University of Pittsburgh and Revivicor, Inc., Blacksburg, VA.

Conflict of Interest

DA is an employee of Revivicor Inc., Blacksburg, VA. The other authors report no conflicts of interest.

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Authors and Affiliations

  1. The Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Starzl Biomedical Science Tower, W1543, 200 Lothrop Street, Pittsburgh, PA, 15261, USA

    Jiang Li, Mohamed B. Ezzelarab & David K. C. Cooper

  2. Department of Transplantation Surgery, Tianjin First Central Hospital, Tianjin Medical University, Tianjin, China

    Jiang Li

  3. Revivicor Inc., Blacksburg, VA, USA

    David Ayares

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  1. Jiang Li
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  2. Mohamed B. Ezzelarab
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  3. David Ayares
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  4. David K. C. Cooper
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Correspondence to David K. C. Cooper.

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Li, J., Ezzelarab, M.B., Ayares, D. et al. The Potential Role of Genetically-Modified Pig Mesenchymal Stromal Cells in Xenotransplantation. Stem Cell Rev and Rep 10, 79–85 (2014). https://doi.org/10.1007/s12015-013-9478-8

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