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1.
iScience ; 16: 192-205, 2019 Jun 28.
Article in English | MEDLINE | ID: mdl-31195238

ABSTRACT

Maturity-onset diabetes of the young 1 (MODY1) is a monogenic diabetes condition caused by heterozygous HNF4A mutations. We investigate how HNF4A haploinsufficiency from a MODY1/HNF4A mutation influences the development of foregut-derived liver and pancreatic cells through differentiation of human induced pluripotent stem cells from a MODY1 family down the foregut lineage. In MODY1-derived hepatopancreatic progenitors, which expressed reduced HNF4A levels and mislocalized HNF4A, foregut genes were downregulated, whereas hindgut-specifying HOX genes were upregulated. MODY1-derived hepatocyte-like cells were found to exhibit altered morphology. Hepatic and ß cell gene signatures were also perturbed in MODY1-derived hepatocyte-like and ß-like cells, respectively. As mutant HNF4A (p.Ile271fs) did not undergo complete nonsense-mediated decay or exert dominant negativity, HNF4A-mediated loss of function is likely due to impaired transcriptional activation of target genes. Our results suggest that in MODY1, liver and pancreas development is perturbed early on, contributing to altered hepatic proteins and ß cell defects in patients.

2.
J Invest Dermatol ; 138(8): 1851-1861, 2018 08.
Article in English | MEDLINE | ID: mdl-29526760

ABSTRACT

Cdc20 and Cdh1 activate the anaphase-promoting complex/cyclosome, a master cell cycle regulator. Although cell cycle modifications occur during differentiation of stem cells, a role for the anaphase-promoting complex/cyclosome on stem cell fate has not been established in embryonic or adult human tissues. We found that differentiated human primary keratinocytes from the skin express extremely low levels of Cdc20 compared with human primary keratinocyte stem cells (holoclones). In agreement with this, staining of human skin biopsies showed that Cdc20 is expressed in occasional cells from the basal and epibasal layers of the epidermis and is absent from the differentiated layers. Conversely, Cdh1 is preferentially expressed in differentiated cells. Interestingly, partial silencing of Cdc20 enhanced differentiation, indicating that loss of Cdc20 might be a cause rather than a consequence of terminal differentiation. By contrast, Cdh1 silencing induced the opposite cellular phenotype, which was characterized by an increase in stemness, cellular proliferation, and loss of differentiation markers. These data pinpoint the anaphase-promoting complex/cyclosome as a key regulator of adult stem cell fate. They also demonstrate the critical and opposing roles of Cdc20 and Cdh1 in controlling the balance between human primary keratinocyte proliferation and differentiation, and therefore in regulating skin homeostasis.


Subject(s)
Anaphase-Promoting Complex-Cyclosome/physiology , Cell Differentiation/physiology , Keratinocytes/physiology , Stem Cells/physiology , 3T3 Cells , Adult , Animals , Antigens, CD/genetics , Antigens, CD/metabolism , Cadherins/genetics , Cadherins/metabolism , Cdc20 Proteins/genetics , Cdc20 Proteins/metabolism , Cell Proliferation/physiology , Child , Epidermis/physiology , Female , Flow Cytometry , Healthy Volunteers , Humans , Male , Mice , Primary Cell Culture
3.
Diabetes Obes Metab ; 20(1): 3-13, 2018 01.
Article in English | MEDLINE | ID: mdl-28474496

ABSTRACT

Type 1 and type 2 diabetes are caused by a destruction and decrease in the number of functional insulin-producing ß cells, respectively; therefore, the generation of functional ß cells from human embryonic stem cells and human induced pluripotent stem cells, collectively known as human pluripotent stem cells (hPSCs), for potential cell replacement therapy and disease modelling is an intensely investigated area. Recent scientific breakthroughs enabled derivation of large quantities of human pancreatic ß-like cells in vitro, although with varied glucose-stimulated insulin secretion kinetics. In the present review, we comprehensively summarize, compare and critically analyze the intricacies of these developing technologies, including differentiation platforms, robustness of protocols, and methodologies used to characterize hPSC-derived ß-like cells. We also discuss experimental issues that need to be resolved before these ß-like cells can be used clinically.


Subject(s)
Insulin-Secreting Cells/cytology , Insulin/metabolism , Models, Biological , Pluripotent Stem Cells/cytology , Animals , Cell Culture Techniques/trends , Cell Differentiation/drug effects , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 1/therapy , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/pathology , Diabetes Mellitus, Type 2/therapy , Drug Discovery/trends , Humans , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Insulin Secretion , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Insulin-Secreting Cells/transplantation , Pluripotent Stem Cells/drug effects , Pluripotent Stem Cells/metabolism , Pluripotent Stem Cells/transplantation
4.
J Hepatol ; 68(5): 1033-1048, 2018 05.
Article in English | MEDLINE | ID: mdl-29175243

ABSTRACT

The hepatocyte nuclear factors (HNFs) namely HNF1α/ß, FOXA1/2/3, HNF4α/γ and ONECUT1/2 are expressed in a variety of tissues and organs, including the liver, pancreas and kidney. The spatial and temporal manner of HNF expression regulates embryonic development and subsequently the development of multiple tissues during adulthood. Though the HNFs were initially identified individually based on their roles in the liver, numerous studies have now revealed that the HNFs cross-regulate one another and exhibit synergistic relationships in the regulation of tissue development and function. The complex HNF transcriptional regulatory networks have largely been elucidated in rodent models, but less so in human biological systems. Several heterozygous mutations in these HNFs were found to cause diseases in humans but not in rodents, suggesting clear species-specific differences in mutational mechanisms that remain to be uncovered. In this review, we compare and contrast the expression patterns of the HNFs, the HNF cross-regulatory networks and how these liver-enriched transcription factors serve multiple functions in the liver and beyond, extending our focus to the pancreas and kidney. We also summarise the insights gained from both human and rodent studies of mutations in several HNFs that are known to lead to different disease conditions.


Subject(s)
Hepatocyte Nuclear Factors/metabolism , Liver/metabolism , Animals , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Gene Expression Regulation, Developmental , Gene Regulatory Networks , Hepatocyte Nuclear Factors/chemistry , Hepatocyte Nuclear Factors/genetics , Humans , Kidney/metabolism , Liver/growth & development , Metabolic Networks and Pathways , Mutation , Pancreas/metabolism , Tissue Distribution
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