Oct4 and Hnf4α-induced hepatic stem cells ameliorate chronic liver injury in liver fibrosis model

Autor: Donggyu Nam, Man Sze Wong, Soo Yong Park, Hans R. Schöler, Myung Rae Park, Jeong Beom Kim, Holm Zaehres, Hong Dae Seo, Hans Florian Zeilhofer, Hyunah Lee, Sang Min Lee, Marcos J. Araúzo-Bravo
Rok vydání: 2019
Předmět:
0301 basic medicine
Liver Cirrhosis
Male
Somatic cell
medicine.medical_treatment
Cellular differentiation
Cell
Gene Expression
Liver transplantation
Biochemistry
Liver disease
Mice
0302 clinical medicine
Animal Cells
Medicine and Health Sciences
Connective Tissue Cells
Staining
Multidisciplinary
Chemistry
Carbon Tetrachloride Poisoning
Liver Diseases
Cell Differentiation
Lung Injury
Specimen preparation and treatment
medicine.anatomical_structure
Hepatocyte Nuclear Factor 4
Liver
Connective Tissue
Hepatocyte
Medicine
Liver Fibrosis
030211 gastroenterology & hepatology
Stem cell
Cellular Types
Anatomy
Research Article
Science
Induced Pluripotent Stem Cells
Surgical and Invasive Medical Procedures
Gastroenterology and Hepatology
03 medical and health sciences
Digestive System Procedures
Albumins
medicine
Genetics
Animals
Transplantation
DAPI staining
Biology and Life Sciences
Proteins
Cell Biology
Organ Transplantation
Fibroblasts
medicine.disease
Liver Transplantation
Research and analysis methods
030104 developmental biology
Biological Tissue
Nuclear staining
Cancer research
Hepatocytes
Octamer Transcription Factor-3
Lipoprotein
Stem Cell Transplantation
Developmental Biology
Zdroj: PLoS ONE
PLoS ONE, Vol 14, Iss 8, p e0221085 (2019)
ISSN: 1932-6203
Popis: Direct conversion from fibroblasts to generate hepatocyte like-cells (iHeps) bypassing the pluripotent state has been described in previous reports as an attractive method acquiring hepatocytes for cell-based therapy. The limited proliferation of iHeps, however, has hampered it uses in cell-based therapy. Since hepatic stem cells (HepSCs) possess self-renewal and bipotency with the capacity to differentiate into both hepatocytes and cholangiocytes, they have therapeutic potential for treating liver disease. Here, we investigated the therapeutic effects of induced HepSCs (iHepSCs) on a carbon tetrachloride (CCl4)-induced liver fibrosis model. We demonstrate that Oct4 and Hnf4a are sufficient to convert fibroblasts into expandable iHepSCs. Hepatocyte-like cells derived from iHepSCs (iHepSC-HEPs) exhibit the typical morphology of hepatocytes and hepatic functions, including glycogen storage, low-density lipoprotein (LDL) uptake, Indocyanine green (ICG) detoxification, drug metabolism, urea production, and albumin secretion. iHepSCs-derived cholangiocyte-like cells (iHepSC-CLCs) expressed cholangiocyte-specific markers and formed cysts and tubule-like structures with apical-basal polarity and secretory function in three-dimensional culture condition. Furthermore, iHepSCs showed anti-inflammatory and anti-fibrotic effects in CCl4-induced liver fibrosis. This study demonstrates that Oct4 and Hnf4α-induced HepSCs show typical hepatic and biliary functionality in vitro. It also presents the therapeutic effect of iHepSCs in liver fibrosis. Therefore, directly converting iHepSCs from somatic cells may facilitate the development of patient-specific cell-based therapy for chronic liver damage.
Databáze: OpenAIRE
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