Integrative Analysis Of Multi-molecular Profiles Of Human Bone Marrow Stem Cells Rescuing Fulminant Hepatic Failure Pigs

With the rapid development of high throughput molecular profiling techniques,integrative analysis of high throughput molecular profiling comes into more and more researchers' vision.Comparing to utilizing a single high throughput method,this approach provides a much more comprehensive and powerful view in studying the mechanism of complex diseases and promoting precise medicine.Stem cell transplantation holds substantial promise in clinical treatment of many lethal diseases.Nonetheless,the mechanisms through which stem cells assist organ repair are still elusive.Fulminant hepatic failure is an aggressive,high-lethal disease.Currently orthotopic liver transplantation is the only effective treatment.Previously,our cooperative laboratory showed that xenotransplantation of human bone marrow mesenchymal stem cells(hBMSCs)rescued D-galactosamine(D-Gal)induced liver damage in pigs(a large animal model of fulminant hepatic failure,FHF).Here we delineate this drug-like therapeutic action with multiple molecular profiles from complementary biological perspectives.Firstly,this study investigated the time window that stem cells take action.We showed that levels of liver-function related biomarkers in serum samples of control group and transplantation group were all significantly elevated at day 3 comparing to day 0 after FHF-induced.Noticeably,these biomarkers in transplantation group also significantly attenuated comparing to control group at day 3,returned to baseline level at day 7 comparing to day 0.Consistent with observation of biomarkers' change,cytokine storms accompanying FHF were observed at day 3,but were suppressed at day 7 with transplantation,when the transplanted hBMSCs completed proliferation and transdifferentiation.Secondly,this study further explored the proliferation,transdifferentiation and paracrine effects of stem cells rescuing FHF.The study indicated that the completion of transdifferentiation of hBMSCs at day 7,resulting approximately 4.5%of the liver cells,and peripheral metabolic homeostasis restored.In the transplantation group,cytokine responses to FHF were markedly different from the control group,suggesting the capacity of hBMSCs to program liver restoration with a different schedule.Finally,by using a novel approach that analyzes the collective functional impact of coordinated gene expression,we found evidence of Notch pathway activation in the hBMSC-directed liver restoration program.Jugular vein injection of D114,a Notch ligand,notably extended the survival time of D-Gal induced FHF subjects in pigs and rats(P = 0.0240,pig;P = 0.0453,rat),suggesting its translational potential.Altogether,this study presents an integrated outline of the transdifferentiation and paracrine effects of stem cells rescuing acute organ damage,providing a basis for further translational study.Our approach that dissects the complex signaling interplay between stem cells and the host organ,exposing the beneficial role of D114-Notch activation,may also facilitate investigation of stem cell mechanisms in other scenarios.