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Islet-Like Structures Generated In Vitro from Adult Human Liver Stem Cells Revert Hyperglycemia in Diabetic SCID

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Adult human liver stem-like cells (HLSC) can form 3D structures that produce insulin. These HLSC-derived insulin-producing structures reversed hyperglycemia in diabetic mice, offering a potential new diabetes therapy.

Keywords:
3D cultureDiabetesInsulin-producing stem cellsLiver stem cellsPancreatic isletsPancreatic β cells

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Area of Science:

  • Regenerative Medicine
  • Endocrinology
  • Stem Cell Biology

Background:

  • Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycemia.
  • Cellular therapies, particularly those involving insulin-producing cells, are a promising strategy for diabetes treatment.
  • Adult human liver stem-like cells (HLSC) share embryonic origins with pancreatic cells, suggesting potential for differentiation.

Purpose of the Study:

  • To investigate the potential of adult human liver stem-like cells (HLSC) to generate insulin-producing 3D spheroid structures (HLSC-ILS).
  • To evaluate the in vitro and in vivo functionality of these HLSC-ILS as a potential diabetes therapy.

Main Methods:

  • A one-step protocol using protamine-induced charge-dependent aggregation of HLSC to form 3D spheroids (HLSC-ILS).
  • Assessment of insulin production, C-peptide secretion, and expression of pancreatic β-cell markers in HLSC-ILS.
  • In vivo studies involving implantation of HLSC-ILS into streptozotocin-diabetic SCID mice to evaluate efficacy in reversing hyperglycemia.

Main Results:

  • HLSC-ILS spontaneously differentiated into cells expressing insulin and key pancreatic β-cell markers, exhibiting endocrine granules.
  • HLSC-ILS demonstrated glucose-stimulated C-peptide production in vitro.
  • Implantation of HLSC-ILS significantly reduced hyperglycemia and restored normoglycemia in diabetic mice, with effects reversible upon explant.

Conclusions:

  • Protamine-induced spheroid aggregation of HLSC effectively triggers spontaneous differentiation into an endocrine phenotype.
  • Despite immaturity, in vitro differentiated HLSC-ILS exhibit glucose-responsive insulin secretion and in vivo efficacy in reversing hyperglycemia in a mouse model of diabetes.
  • HLSC-derived insulin-producing structures represent a viable cell source for potential diabetes regenerative therapy.