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

(Pages: 1-13)
Fattah Sotoodehnejadnematalahi, Ph.D, 1,#Reza Moghadasali, Ph.D, 2,3,4,*Mostafa Hajinasrollah, D.V.M, 2Ehsan Ehsani, Ph.D., 2,5Ensiyeh Hajizadeh-Saffar, M.D., Ph.D., 3Niloofar Sodeifi, M.D., 6Reza F. Saidi, M.D., 7Morteza Zarrabi, Ph.D., 8Mohammad Farzanehkhah, M.Sc., 8Bahareh Sadeghi, M.Sc., 8Hossein Baharvand, Ph.D., 1,4Nasser Aghdami, M.D., Ph.D., 4
Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
Department of Stem Cells and Developmental Biology, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
Department of Regenerative Medicine, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
Department of Developmental Biology, University of Science and Culture, Tehran, Iran
Department of Biology, Roudehen Branch, Islamic Azad University, Roudehen, Iran
Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
Department of Surgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
Royan Stem Cell Technology Company, Cord Blood Bank, Tehran, Iran
Department of Biology, School of Basic Science, Science and Research Branch, Islamic Azad University, Tehran, Iran
Department of Stem Cells and Developmental Biology, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
Department of Regenerative Medicine, Cell Sciences Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
Department of Developmental Biology, University of Science and Culture, Tehran, Iran
Department of Biology, Roudehen Branch, Islamic Azad University, Roudehen, Iran
Department of Andrology, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
Department of Surgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
Royan Stem Cell Technology Company, Cord Blood Bank, Tehran, Iran
*Corresponding Address: P.O.Box: 16635-148 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

The first two authors equally contributed to this work.

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Sotoodehnejadnematalahi Fattah, Moghadasali Reza, Hajinasrollah Mostafa, Ehsani Ehsan, Hajizadeh-Saffar Ensiyeh, Sodeifi Niloofar, Saidi Reza F., Zarrabi Morteza, Farzanehkhah Mohammad, Sadeghi Bahareh, Baharvand Hossein, Aghdami Nasser. Immunomodulatory Activity of Human Bone Marrow and Adipose-Derived Mesenchymal Stem Cells Prolongs Allogenic Skin Graft Survival in Nonhuman Primates. Cell J. 2021; 23(1): 1-13.

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&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.