Human Pluripotent Stem Cells Go Diabetic: A Glimpse on Monogenic Variants

Heller, Sandra; Melzer, Michael Karl; Azoitei, Ninel; Julier, Cécile; Kleger, Alexander

doi:10.3389/fendo.2021.648284

Cited by 3 publications

(2 citation statements)

References 181 publications

(168 reference statements)

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“…Remarkably, many of these genes encode key proteins for pancreas development (for example, HNF1A, HNF1B, HNF4A and GLIS3). Human pluripotent stem cells (PSCs) represent a powerful tool to simulate pancreatic development and facilitate disease modeling [7][8][9] .…”

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confidence: 99%

Mutations and variants of ONECUT1 in diabetes

Philippi

Heller

Costa

et al. 2021

Nat Med

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Genes involved in distinct diabetes types suggest shared disease mechanisms. Here we show that One Cut Homeobox 1 (ONECUT1) mutations cause monogenic recessive syndromic diabetes in two unrelated patients, characterized by intrauterine growth retardation, pancreas hypoplasia and gallbladder agenesis/hypoplasia, and early-onset diabetes in heterozygous relatives. Heterozygous carriers of rare coding variants of ONECUT1 define a distinctive subgroup of diabetic patients with early-onset, nonautoimmune diabetes, who respond well to diabetes treatment. In addition, common regulatory ONECUT1 variants are associated with multifactorial type 2 diabetes. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. Loss of ONECUT1 altered transcription factor binding and enhancer activity and NKX2.2/NKX6.1 expression in pancreatic progenitor cells. Collectively, we demonstrate that ONECUT1 controls a transcriptional and epigenetic machinery regulating endocrine development, involved in a spectrum of diabetes, encompassing monogenic (recessive and dominant) as well as multifactorial inheritance. Our findings highlight the broad contribution of ONECUT1 in diabetes pathogenesis, marking an important step toward precision diabetes medicine.

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confidence: 99%

Mutations and variants of ONECUT1 in diabetes

Philippi

Heller

Costa

et al. 2021

Nat Med

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“…However, induced pluripotent stem cells (iPSCs) generated from monogenic diabetes models is an important breakthrough. By differentiating iPSCs into pancreatic beta-like cells, researchers can delve into disease mechanisms such as impaired insulin secretion or beta-cell dysfunction in a controlled laboratory setting[ 33 ]. This understanding can serve as a cornerstone for developing novel treatments, not only for monogenic diabetes but also for advancing personalized medicine approaches in the broader context of type 1 and type 2 diabetes[ 34 ].…”

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confidence: 99%

Monogenic diabetes in children: An underdiagnosed and poorly managed clinical dilemma

Bhattacharya,

Pappachan

2024

World J Diabetes

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Monogenic diabetes, constituting 1%-2% of global diabetes cases, arises from single gene defects with distinctive inheritance patterns. Despite over 50 ass-ociated genetic disorders, accurate diagnoses and management of monogenic diabetes remain inadequate, underscoring insufficient clinician awareness. The disease spectrum encompasses maturity-onset diabetes of the young (MODY), characterized by distinct genetic mutations affecting insulin secretion, and neonatal diabetes mellitus (NDM) – a heterogeneous group of severe hyperglycemic disorders in infants. Mitochondrial diabetes, autoimmune monogenic diabetes, genetic insulin resistance and lipodystrophy syndromes further diversify the monogenic diabetes landscape. A tailored approach based on phenotypic and biochemical factors to identify candidates for genetic screening is recommended for suspected cases of MODY. NDM diagnosis warrants immediate molecular genetic testing for infants under six months. Identifying these genetic defects presents a unique opportunity for precision medicine. Ongoing research aimed to develop cost-effective genetic testing methods and gene-based therapy can facilitate appropriate identification and optimize clinical outcomes. Identification and study of new genes offer a valuable opportunity to gain deeper insights into pancreatic cell biology and the pathogenic mechanisms underlying common forms of diabetes. The clinical review published in the recent issue of World Journal of Diabetes is such an attempt to fill-in our knowledge gap about this enigmatic disease.

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Transcriptional changes and the role of ONECUT1 in hPSC pancreatic differentiation

Heller

Lin

et al. 2021

Commun Biol

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Cell type specification during pancreatic development is tightly controlled by a transcriptional and epigenetic network. The precise role of most transcription factors, however, has been only described in mice. To convey such concepts to human pancreatic development, alternative model systems such as pancreatic in vitro differentiation of human pluripotent stem cells can be employed. Here, we analyzed stage-specific RNA-, ChIP-, and ATAC-sequencing data to dissect transcriptional and regulatory mechanisms during pancreatic development. Transcriptome and open chromatin maps of pancreatic differentiation from human pluripotent stem cells provide a stage-specific pattern of known pancreatic transcription factors and indicate ONECUT1 as a crucial fate regulator in pancreas progenitors. Moreover, our data suggest that ONECUT1 is also involved in preparing pancreatic progenitors for later endocrine specification. The dissection of the transcriptional and regulatory circuitry revealed an important role for ONECUT1 within such network and will serve as resource to study human development and disease.

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Human Pluripotent Stem Cells Go Diabetic: A Glimpse on Monogenic Variants

Cited by 3 publications

References 181 publications

Mutations and variants of ONECUT1 in diabetes

Mutations and variants of ONECUT1 in diabetes

Monogenic diabetes in children: An underdiagnosed and poorly managed clinical dilemma

Transcriptional changes and the role of ONECUT1 in hPSC pancreatic differentiation

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