Immunomodulatory Activity of Human Bone Marrow and Adipose-Derived Mesenchymal Stem Cells Prolongs Allogenic Skin Graft Survival in Nonhuman Primates

Fattah Sotoodehnejadnematalahi; Reza Moghadasali; Mostafa Hajinasrollah; Ehsan Ehsani; Ensiyeh Hajizadeh-Saffar; Niloofar Sodeifi; Reza Saidi; Morteza Zarrabi; Mohammad Farzanehkhah; Bahareh Sadeghi; Hossein Baharvand; Nasser Aghdami

doi:10.22074/cellj.2021.6895

Immunomodulatory Activity of Human Bone Marrow and Adipose-Derived Mesenchymal Stem Cells Prolongs Allogenic Skin Graft Survival in Nonhuman Primates

Cell J. 2021 Apr;23(1):1-13. doi: 10.22074/cellj.2021.6895. Epub 2021 Mar 1.

Authors

Affiliations

¹ Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran.
² Department of Stem Cells and Developmental Biology, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran. Email: rezamoghadasali@royaninstitute.org.
³ Department of Regenerative Medicine, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
⁴ Department of Developmental Biology, University of Science and Culture, Tehran, Iran.
⁵ Department of Stem Cells and Developmental Biology, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
⁶ Department of Biology, Roudehen Branch, Islamic Azad University, Roudehen, Iran.
⁷ Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.
⁸ Department of Surgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
⁹ Royan Stem Cell Technology Company, Cord Blood Bank, Tehran, Iran.

^# Contributed equally.

Abstract

Objective: In the present study, we examined the tolerance-inducing effects of human adipose-derived mesenchymal stem cells (hAD-MSCs) and bone marrow-derived MSCs (hBM-MSCs) on a nonhuman primate model of skin transplantation.

Materials and methods: In this experimental study, allogenic and xenogeneic of immunomodulatory properties of human AD-MSCs and BM-MSCs were evaluated by mixed lymphocyte reaction (MLR) assays. Human MSCs were obtained from BM or AD tissues (from individuals of either sex with an age range of 35 to 65 years) and intravenously injected (2×106 MSCs/kg) after allogeneic skin grafting in a nonhuman primate model. The skin sections were evaluated by H and E staining for histopathological evaluations, particularly inflammation and rejection reaction of grafts after 96 hours of cell injection. At the mRNA and protein levels, cellular mediators of inflammation, such as CD4+IL-17+ (T helper 17; Th17) and CD4+INF-γ+ (T helper 1, Th1) cells, along with CD4+FoxP3+ cells (Treg), as the mediators of immunomodulation, were measured by RT-PCR and flow cytometry analyses.

Results: A significant Treg cells expansion was observed in MSCs-treated animals which reached the zenith at 24 hours and remained at a high concentration for 96 hours; however, Th1 and Th17 cells were significantly decreased. Our results showed that human MSCs significantly decrease Th1 and Th17 cell proliferation by decreasing interleukin-17 (IL-17) and interferon-γ (INF-γ) production and significantly increase Treg cell proliferation by increasing FoxP3 production. They also extend the allogenic skin graft survival in nonhuman primates. Histological evaluations showed no obvious presence of inflammatory cells or skin redness or even bulging after MSCs injection up to 96 hours, compared to the group without MSCs. There were no significant differences between hBM-MSCs and hAD-MSCs in terms of histopathological scores and inflammatory responses (P<0.05).

Conclusion: It seems that MSCs could be regarded as a valuable immunomodulatory tool to reduce the use of immunosuppressive agents.

Keywords: Adipose; Allogenic; Bone Marrow; Immunomodulation; Mesenchymal Stem Cells.