Cell therapy for acute liver injury - in vivo efficacy of mesenchymal stromal cells in toxic and immune-mediated murine hepatitis

Alfaifi, Mohammed (2018). Cell therapy for acute liver injury - in vivo efficacy of mesenchymal stromal cells in toxic and immune-mediated murine hepatitis. University of Birmingham. Ph.D.

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Abstract

The ability of umbilical cord-derived mesenchymal stromal cells (UC-MSCs) to immunomodulate offers therapeutic potential in liver injury but the inherent heterogeneity of unsorted MSC populations may explain varied/reduced function as well as posing regulatory challenges. Thus, we aimed to evaluate the therapeutic potential of purified CD362+ MSC infusion in murine models of acute liver injury. UC-MSCs were injected intravenously into mice injured by single dose of Carbon tetrachloride (CCl4) & OVA-BIL mice. MSC used were either unsorted or sorted CD362+. The extent of liver damage was determined by liver histology, serum analysis, gene expression and FACS analysis 3 or 5 days after cell infusion. Homing and bio-distribution of stem cells was determined by whole mouse cryo-imaging of Q-dot labelled MSC following infusion of UC-MSC into injured mice. CD362+ MSC were as effective as unsorted MSC in ameliorating liver injury, with reductions in serum ALT seen in both models. In contrast heat-inactivated MSC had no effect on liver injury. MSC also led to a reduction in CD45+staining on liver sections in both models of liver injury corroborated by an accompanying reduction in hepatic CD45+ cells in (FACS analysis of liver digest). In addition, there was a significant reduction in hepatic CD19+ B cells in digested liver in CCl4 injury. CD362+ MSCs were found to have the ability to reduce the level of adhesion molecules (ICAM and VCAM) in Ova-Bil mice. Cryo-imaging of time-course in both animal models indicated that MSC had migrated to the lung within 1 hour and were then cleared rapidly, although there was a liverspecific increase in MSC 2-3 day in Ova-Bil mice. CD362+ human MSC exert potent anti-inflammatory activity in toxic and immune-mediated murine liver injury with demonstrable reductions in infiltrating inflammatory leucocytes and B cells.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
Supervisor(s):
Supervisor(s)EmailORCID
Newsome, PhilUNSPECIFIEDUNSPECIFIED
Frampton, JonUNSPECIFIEDUNSPECIFIED
Licence:
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: Institute of Immunology and Immunotherapy
Funders: Other
Other Funders: Government of Saudi Arabia, King Khalid University, Saudi Arabia, Royal Embassy of Saudi Arabia - Cultural Bureau in London (UK)
Subjects: Q Science > Q Science (General)
Q Science > QR Microbiology > QR180 Immunology
URI: http://etheses.bham.ac.uk/id/eprint/8330

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