University Professor of Pharmacology
Mesenchymal stem cells (MSCs), also called multipotent mesenchymal stromal cells, exist in almost all tissues and are a key cell source for tissue repair and regeneration. Under pathological conditions, such as tissue injury, these cells are mobilized towards the site of damage. Tissue damage is usually accompanied by pro-inflammatory factors, produced by both innate and adaptive immune responses, to which MSCs are known to respond. Our studies have shown that there are bidirectional interactions between MSCs and inflammatory cells, which determine the outcome of MSC-mediated tissue repair processes. Since mesenchymal stem cells actively migrate to tumors, we are studying these cells in the tumor microenvironment and their role in tumor growth and metastasis.
We have reported that mesenchymal stem cells have a dramatic effect on lymphocyte activation and proliferation. In vivo administration of mesenchymal stem cells could prevent the rejection of allogeneic skin grafts. Such an immunosuppressive effect was not innate to mesenchymal stem cells, rather induced by cytokines produced by lymphocytes. We are investigating the cellular and molecular mechanisms that mediate such strong immunosuppressive effects by this specialized cell population. In addition, we are also developing new strategies for clinical treatment of critical diseases such liver cirrhosis and Parkinson’s disease.
Investigating the molecular mechanisms that controls activation-induced cell death (AICD) in various T cell types has been one of the major focuses of our laboratory. Our recent efforts have been on elucidating the differences of the mechanisms that control AICD in Th1 and Th2 cells as well as Tc1 and Tc2 cells. We have shown that while Th1 cells die by the Fas-mediated caspase pathway, Th2 cells die through intracellular release of granzyme B. They also found that prostaglandin E2 (PGE2) specifically protected Th2 cells from AICD by downregulating granzyme B. Thus, differences in the expression of, and susceptibility to, death effectors are a built-in mechanism that controls the Th1-Th2 as well as Tc1-Tc2 balance. One example is severer antigen induced asthma in granzyme B deficient mice.
Shi YB, Shi Y, Scott DW, and Xu Y. 1997. Programmed Cell Death. Plenum Press, New York.
Shi Y, Cidlowski J, Scott DW, and Shi YB. 2003. Molecular Mechanisms of Programmmed Cell Death. Kluwer Academic/Plenum Publishers, New York.
Sun E, Zhang L, Roberts AI, Liu C and Shi Y. Chronic stress induced death of lymphocytes. Cytokines: Stress and Immunity Second Edition, edited by Nicholas P Plotnikoff, Robert E Faith, Anthony J Murgo, and Robert A Good. 2005, CRC Press.
Shi Y, Devadas S, Zhang X, Zhang L, Keegan AD, Greeneltch K, Solomon JC, Yuan Z, Sun E, Liu C, Das J, Thayyil-Satish M, Wei L, Zhou J and Roberts AI. Activation-Induced Cell Death and T Helper Subset Differentiation. In Shi YF, Cidlowski J, Scott DW and Shi YB. (Eds.) Molecular Mechanisms of Programmmed Cell Death Kluwer Academic/Plenum Publishers, New York 2003.
Sun E and Shi Y. The mechanisms and significance of immune tolerance induced by apoptotic cells. In Shi YF, Cidlowski J, Scott DW and Shi YB. (Eds.). Molecular Mechanisms of Programmed Cell Death Kluwer Academic/Plenum Publishers, New York 2003.
Wang R, Zhang L, Yin D, Mufson RA and Shi Y. Regulation of Fas and FasL expression during activation-induced T-cell apoptosis. In Talwar GP, Nath I, Ganguly NK and Rao KVS. (Eds.) Proceedings of 10th International Congress of Immunology Monduzzi Editore, Bologna, Italy 1999, pp 499-505.
Shi Y, Mills GB and Wang R. Mitogenic Cytokines Promote Apoptosis: Possible Roles in Cellular Homeostasis. In Shi YB, Shi YF, Scott DW and Xu YH. (Eds.) Current Advances in Programmed Cell Death Plenum Publishing Corp., New York 1997, pp 113-142.
Scott DW, Brunner T, Donjerkovic D, Ezhevsky S, Grdina T, Green DR, Shi Y and Yao X. Murder and suicide: A tale of T and B cell apoptosis. In Shi YB, Shi YF, Scott DW and Xu YH. (Eds.) Current Advances in Programmed Cell Death Plenum Publishing Corp., New York 1997, pp 91-103.
Shi Y and Wang R. Apoptosis and immune regulation. In Li C, Guo Y, Yie Q and Tang X. (Eds.) Current Advance in Tumor Molecular Biology Medical Science Publisher, Beijing 1996, pp 61-69.
Scott DW, Ezhevksy S, Maddox B, Washart K, Yao X and Shi Y. Scenes from short life: checkpoints and progression signals for immature B-cell life versus apoptosis. In Rigley K, and Harnett M. (Eds.). John Wiley, Chichester, England. 1995, pp 165-175.
Green DR, Shi Y, Glynn JM, Mahboubi A and Mogil RJ. Myc, Fas, apoptosis, and immune tolerance. In: Apoptosis. In Mihich E and Schimke RT. (Eds.) Apoptosis Plenum Press, New York 1994, pp 213-222.
Bissonnette RP, Shi Y, Mahboubi A, Glynn JM. C-myc and apoptosis. Current Communications in Cell and Molecular Biology 1994, 327-327.
Bissonnette RP, Shi Y, Mahboubi A, Glynn JM and Green DR. C-myc and apoptosis. In Tomei LD and Cope FO. (Eds.) Apoptosis II: The Molecular Basis of Cell Death Cold Spring Harbor Lab Press, Cold Spring Harbor, New York 1994, pp 327-335.
Green DR and Shi Y. Activation-induced cell death in developing T cells and T cell hybridomas. In Malhotra SK. (Ed.) Advances in Structural Biology JAI Press, Inc. 1990, pp 287-299.