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Clustering-mediated Functional Maturation of Pluripotent Stem Cell-derived Pancreatic Cells

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Review of “Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived β cells” from Nature Cell Biology by Stuart P. Atkinson 

Replacement of the pancreatic β cells whose destruction and/or dysfunction results in the development of type 1 and type 2 diabetes remains as an unmet medical need. While various studies have underlined the vast potential of human pluripotent stem cell-derived pancreatic β cells [1-3], current protocols generate cells lacking the required functionality. 

As recent studies on pancreas organogenesis have suggested that pancreatic cell aggregation/clustering may drive functional maturation [4, 5], researchers from the laboratory of Matthias Hebrok (University of California San Francisco, San Francisco, CA, USA) sought to alter their stem cell culture conditions to mimic the in vivo situation. Encouragingly, the team’s new Nature Cell Biology article now establishes that immature human pluripotent stem cell-derived pancreatic β cell clustering in vitro promotes the generation of mature β cells that resemble their endogenous counterparts [6].

Nair et al. aimed to generate mature functional β cells by recreating the events taking place during pancreatic islet organogenesis and β cell maturation in vivo. To this end, the team isolated and reaggregated human pluripotent stem cell-derived immature β-like cells to form islet-sized enriched β-clusters as a means to recapitulate endocrine cell clustering and promote maturation. Resultant in vitro mature cells within enriched β-clusters closely resembled primary adult β cells at the transcriptomic, physiological and functional levels, with the latter evidenced by analysis of in vitro insulin secretion, calcium signaling, and mitochondrial energization, 

Mechanistically, the study discovered that the formation of enriched β-clusters via clustering promoted metabolic maturation, a reportedly fundamental process for stimulus-secretion coupling in mature β cells, evidenced by increased mitochondrial respiration, mitochondrial mass, and differential membrane depolarization on glucose stimulation.

Moving in vivo, transplantation of enriched β-clusters into mice led to the generation of islet-like grafts containing β cells, as well as glucagon-producing α and somatostatin-producing δ cells. Encouragingly, said grafts displayed glucose-stimulated insulin secretion at just three days post-transplant with no signs of tumorigenic growth eight months later.

Overall, the authors suggest that in vitro clustering of human pluripotent stem cell-derived pancreatic β cells into enriched β-clusters will permit the generation of endogenous like cells for applications in physiology and functional toxicology and may even represent a safe and effective alternative to human islets for cell therapy.

For more on how functional maturation by cell clustering has moved human pluripotent stem cell-derived pancreatic cells closer towards the clinic, stay tuned to the Stem Cells Portal!

References

  1. Pagliuca FW, Millman JR, Gurtler M, et al., Generation of functional human pancreatic beta cells in vitro. Cell 2014;159:428-39.
  2. Rezania A, Bruin JE, Arora P, et al., Reversal of diabetes with insulin-producing cells derived in vitro from human pluripotent stem cells. Nature Biotechnology 2014;32:1121-33.
  3. Russ HA, Parent AV, Ringler JJ, et al., Controlled induction of human pancreatic progenitors produces functional beta-like cells in vitro. EMBO Journal 2015;34:1759-72.
  4. Nair G and Hebrok M, Islet formation in mice and men: lessons for the generation of functional insulin-producing beta-cells from human pluripotent stem cells. Current Opinion in Genetics & Development 2015;32:171-80.
  5. Jeon J, Correa-Medina M, Ricordi C, et al., Endocrine cell clustering during human pancreas development. Journal of Histochemistry & Cytochemistry 2009;57:811-24.
  6. Nair GG, Liu JS, Russ HA, et al., Recapitulating endocrine cell clustering in culture promotes maturation of human stem-cell-derived β cells. Nature Cell Biology 2019;21:263-274.