title: Simulated microgravity promoted differentiation of bipotential murine oval liver stem cells by modulating BMP4/Notch1 signaling.
abstract: Faster growth and differentiation of liver stem cells to hepatocyte is one of the key factors during liver regeneration. In recent years, simulated microgravity, a physical force has shown to differentially regulate the differentiation and proliferation of stem cells. In the present work, we studied the effect of simulated microgravity on differentiation and proliferation of liver stem cells. The cells were subjected to microgravity, which was simulated using indigenously fabricated 3D clinostat. Proliferation, apoptosis, immunofluorescence assays and Western blot analysis were carried out to study the effects of simulated microgravity on liver stem cells. Microgravity treatment for 2 h enhanced proliferation of stem cells by twofold without inducing apoptosis and compromising cell viability. Analysis of hepatocyte nuclear factor 4-α (HNF4-α) expression after 2 h of microgravity treatment revealed that microgravity alone can induce the differentiation of stem cells within 2-3 days. Probing bone morphogenic protein 4 (BMP4) and Notch1 in microgravity treated stem cells elaborated downregulation of Notch1 and upregulation of BMP4 after 2 days of incubation. Further, blocking BMP4 using dorsomorphin and chordin conditioned media from chordin plasmid transfected cells attenuated microgravity mediated differentiation of liver stem cells. In conclusion, microgravity interplays with BMP4/Notch1 signaling in stem cells thus inducing differentiation of stem cells to hepatocytes. Present findings can be implicated in clinical studies where microgravity activated stem cells can regenerate the liver efficiently after liver injury.
authors: Vascular Biology Lab, Life Sciences Division, AU-KBC Research Centre, Anna University, Chennai, Tamil Nadu, India.
authors: Syamantak
authors: S
authors: Majumder
authors: Jamila H
authors: JH
authors: Siamwala
authors: Sundaramoorthy
authors: S
authors: Srinivasan
authors: Swaraj
authors: S
authors: Sinha
authors: Sree Rama Chaitanya
authors: SR
authors: Sridhara
authors: Gowrishankar
authors: G
authors: Soundararajan
authors: Himabindu Reddy
authors: HR
authors: Seerapu
authors: Suvro
authors: S
authors: Chatterjee
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D017209:Apoptosis; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D057075:Enzyme Assays; D006023:Glycoproteins / Q000494:pharmacology; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000737:chemistry / Q000378:metabolism; D008099:Liver / Q000166:cytology*; D051379:Mice; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D018474:Weightlessness Simulation
chemical_list: D000943:Antigens, Differentiation; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D017077:Culture Media, Conditioned; D006023:Glycoproteins; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C497762:Notch1 protein, mouse; D011720:Pyrazoles; D011743:Pyrimidines; D051881:Receptor, Notch1; C516138:dorsomorphin; C054234:chordin; D007770:L-Lactate Dehydrogenase