title: Molecular and Cellular Functions Distinguish Superior Therapeutic Efficiency of Bone Marrow CD45 Cells Over Mesenchymal Stem Cells in Liver Cirrhosis.
abstract: Liver fibrosis is strongly associated with chronic inflammation. As an alternative to conventional treatments for fibrosis, mesenchymal stem cells (MSCs) therapy is found to be attractive due to its immunomodulatory functions. However, low survival rate and profibrogenic properties of MSCs remain the major concerns, leading to skepticism in many investigators. Here, we have asked the question whether bone marrow (BM)-derived CD45 cells is the better candidate than MSCs to treat fibrosis, if so, what are the molecular mechanisms that make such distinction. Using CCl4 -induced liver fibrosis mouse model of a Metavir fibrosis score 3, we showed that BM-CD45 cells have better antifibrotic effect than adipose-derived (AD)-MSCs. In fact, our study revealed that antifibrotic potential of CD45 cells are compromised by the presence of MSCs. This difference was apparently due to significantly high level expressions of matrix metalloproteinases-9 and 13, and the suppression of hepatic stellate cells' (HpSCs) activation in the CD45 cells transplantation group. Mechanism dissection studied in vitro supported the above opposing results and revealed that CD45 cell-secreted FasL induced apoptotic death of activated HpSCs. Further analyses suggest that MSC-secreted transforming growth factor β and insulin-like growth factor-1 promoted myofibroblastic differentiation of HpSCs and their proliferation. Additionally, the transplantation of CD45 cells led to functional improvement of the liver through repair and regeneration. Thus, BM-derived CD45 cells appear as a superior candidate for the treatment of liver fibrosis due to structural and functional improvement of CCl4 -induced fibrotic liver, which were much lower in case of AD-MSC therapy.
authors.affiliation: Stem Cell Biology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: Prakash
authors.initials: P
authors.lastname: Baligar
authors.affiliation: Stem Cell Biology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: Snehasish
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Stem Cell Biology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: Veena
authors.initials: V
authors.lastname: Kochat
authors.affiliation: Department of Pathology, Institute of Liver & Biliary Sciences, Vasant Kunj, New Delhi, India.
authors.forename: Archana
authors.initials: A
authors.lastname: Rastogi
authors.affiliation: Stem Cell Biology Laboratory, National Institute of Immunology, New Delhi, India.
authors.forename: Asok
authors.initials: A
authors.lastname: Mukhopadhyay
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D020732:Cytogenetic Analysis; D053222:Fas Ligand Protein / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D008810:Mice, Inbred C57BL; D010641:Phenotype; D020127:Recovery of Function / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D053222:Fas Ligand Protein; D016212:Transforming Growth Factor beta; D017493:Leukocyte Common Antigens
keywords: Hematopoietic cells; Hepatic stellate cells; Liver fibrosis; Liver regeneration; Macrophages