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Patient-specific hiPSCs Helps to Decipher Diabetes-related Condition

Review of “HNF4A Haploinsufficiency in MODY1 Abrogates Liver and Pancreas Differentiation from Patient-Derived Induced Pluripotent Stem Cells” from iScience by Stuart P. Atkinson

Maturity-onset diabetes of the young 1 (MODY1), an autosomal dominant monogenic diabetes-related condition that typically manifests before the age of 25 years, is caused by mutations in the hepatocyte nuclear factor 4A (HNF4A) transcription factor gene [1] and leads to defects in glucose-stimulated insulin secretion from the pancreatic β cells [2]. As animal models fail to recapitulate the disease phenotype fully, human induced pluripotent stem cell (hiPSC)-based disease modeling strategies [3, 4] have provided a means to investigate the impact of MODY1/HNF4A mutation on the development of the foregut lineage in humans. 

Now researchers led by Adrian Kee Keong Teo (A*STAR/Nanyang Technological University/National University of Singapore, Singapore) sought to understand the molecular and transcriptional alterations caused by heterozygous HNF4A mutation on early foregut endoderm, liver, and pancreas development leading to disease onset in humans through the derivation and differentiation of hiPSCs from members of a MODY1 family [5]. Overall, this new patient-specific hiPSC-based study suggests that a mutation in HNF4A impacts early human foregut development and impacts later hepatic and pancreatic cell fates through the perturbation of normal transcription factor function.

Ng et al. revealed that hepatopancreatic progenitors differentiated from iPSCs derive from MODY1 patients expressed low levels of HNF4A and mislocalized any HNF4A protein away from the nucleus to the cytoplasm when compared to those obtained from control iPSCs derived from MODY1 patient non-diabetic family members, suggesting a possible perturbation in the transcription regulatory role of HNF4. Furthermore, the authors established the downregulation of foregut-, pancreas-, and liver-associated gene expression and the upregulation of hindgut-specifying HOX genes. 

This early developmental perturbation also led to alterations during the differentiation of MODY-iPSC-derived hepatopancreatic progenitors into hepatocytes and pancreatic β-cells - hepatocyte-like cells exhibited an altered morphology and a perturbed gene expression profile, while pancreatic β-like cells also suffered from disruptions to their expected gene expression profile. Given these results, and the fact that the authors failed to find evidence of mutant HNF4A undergoing complete nonsense-mediated decay or exerting dominant negativity, the authors hypothesize that the impaired transcriptional activation of target genes mediates the HNF4A loss-of-function in MODY1.

While this new patient-specific hiPSC-based study reveals some of the molecular and transcriptional alterations caused by MODY1-associated HNF4A mutations, the authors do highlight certain limitations to their studies. With these in mind, the team next hope to employ single-cell studies to overcome the heterogeneous nature of the differentiation process, to apply genome-editing tools to replace family controls with isogenic controls, and to evaluate the insulin secretory capacity of the MODY1-derived cells.

For more on how patient-specific iPSCs can aid the exploration of disease-associated mutations, stay tuned to the Stem Cells Portal!

References

  1. Yamagata K, Furuta H, Oda N, et al., Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1). Nature 1996;384:458-460.
  2. Byrne MM, Sturis J, Fajans SS, et al., Altered Insulin Secretory Responses to Glucose in Subjects with a Mutation in the MODY1 Gene on Chromosome 20. Diabetes 1995;44:699.
  3. DeLaForest A, Nagaoka M, Si-Tayeb K, et al., HNF4A is essential for specification of hepatic progenitors from human pluripotent stem cells. Development 2011;138:4143.
  4. Vethe H, Bjørlykke Y, Ghila LM, et al., Probing the missing mature β-cell proteomic landscape in differentiating patient iPSC-derived cells. Scientific Reports 2017;7:4780.
  5. Ng NHJ, Jasmen JB, Lim CS, et al., HNF4A Haploinsufficiency in MODY1 Abrogates Liver and Pancreas Differentiation from Patient-Derived Induced Pluripotent Stem Cells. iScience 2019;16:192-205.