Life Sciences & Biotechnology
Title : | Unraveling the molecular mechanism(s) behind the immune-switch from immunosuppressive to immunogenic phenotype in differentiated allogenic mesenchymal stem cells intended for bone tissue repair/regeneration |
Area of research : | Life Sciences & Biotechnology |
Focus area : | Immunology |
Principal Investigator : | Dr. Saravanan Sekaran, Sastra University |
Timeline Start Year : | 2019 |
Timeline End Year : | 2021 |
Contact info : | ranklopg@gmail.com |
Details
Executive Summary : | In the recent years, many preclinical and clinical trials examined the therapeutic efficacy of allogenic mesenchymal stem cells (a-MSCs) as a suitable alternative to conventional gold standards for bone repair and regeneration. a-MSCs are either osteo or chondrogenically differentiated to promote bone regeneration by intramembranous or endochondral ossification. Undifferentiated a-MSCs (in resting state) are immunomodulatory and weakly immunogenic in phenotype. They possess low/reduced expression levels of major histocompatibility complex- II (MHC-II) and costimulatory molecules CD80 and CD86. They modulate immune response by directly inhibiting immune sentinels (T cells, NK cells, dendritic cells) proliferation, differentiation and their secretome. They also help in regenerating damaged bone tissue by modulating the microenvironment through various paracrine secretions. Despite numerous claims on the immunoevasiveness of differentiated allogenic MSCs (da-MSCs), contradictory investigations reported that following transplantation it converts to an immunogenic phenotype. Such contrasting pre-clinical outcomes necessitates for a definitive conclusion. Under normal conditions, MHC-II proteins are not expressed on the MSCs surface due to its degradation by 26S proteasomal machinery to sustain immunoprivilege. However, a rich deposit of MHC-II mRNA retains in the cytoplasm and translated immediately upon its exposure to inflammatory environment leading to its rejection. Apart from this, immune response to d-MSCs could vary from patient to patient and the host immune responses to them are less known with no clear molecular investigations reported. Currently no unequivocal mechanisms are studied that describe the immunological consequences upon chondrogenic and osteogenic differentiation. We speculate that, during bone regeneration/healing, the survival and retention of implanted da-MSCs are negatively affected by two detrimental conditions (1) hypoxia and (2) inflammatory microenvironment. Therefore, da-MSCs may begin to express MHC-II on their surface tagging them for immune rejection. We assume that these conditions may upregulate MHC-II levels by intruding in either MHC-II mRNA transcription (CIITA post translational modification), and/or degradation of MHC-II protein by 26S proteasome. Hence, the current proposal is designed to answer the following questions (1) What happens to immunoprivilege of da-MSCs upon differentiation, hypoxia and IFN-γ exposure, (2) what is the functional status of 26S proteasome machinery stability and activity under these conditions (MHC-II turnover), (3) how CIITA post translational modification is regulated under these conditions. Unfolding these questions might remove impediments that inhibit the progression of the use of da-MSCs towards clinical applications. The proposal is expected to shed insights in to the clinical translation of da-MSCs for bone repair and regeneration. |
Co-PI: | Dr. Manoj Kumar Moharana National Institute Of Technology Rourkela, Odisha,Sector - 2, Rourkela,Odisha,Sundargarh (Sundergarh)-769008 |
Total Budget (INR): | 24,29,229 |
Organizations involved