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

Victor Navarro-Tableros, Chiara Gai, Yonathan Gomez, Sara Giunti, Chiara Pasquino, Maria Chiara Deregibus, Marta Tapparo, Adriana Pitino, Ciro Tetta, Maria Felice Brizzi, Camillo Ricordi, Giovanni Camussi

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

A potential therapeutic strategy for diabetes is the transplantation of induced-insulin secreting cells. Based on the common embryonic origin of liver and pancreas, we studied the potential of adult human liver stem-like cells (HLSC) to generate in vitro insulin-producing 3D spheroid structures (HLSC-ILS). HLSC-ILS were generated by a one-step protocol based on charge dependent aggregation of HLSC induced by protamine. 3D aggregation promoted the spontaneous differentiation into cells expressing insulin and several key markers of pancreatic β cells. HLSC-ILS showed endocrine granules similar to those seen in human β cells. In static and dynamic in vitro conditions, such structures produced C-peptide after stimulation with high glucose. HLSC-ILS significantly reduced hyperglycemia and restored a normo-glycemic profile when implanted in streptozotocin-diabetic SCID mice. Diabetic mice expressed human C-peptide and very low or undetectable levels of murine C-peptide. Hyperglycemia and a diabetic profile were restored after HLSC-ISL explant. The gene expression profile of in vitro generated HLSC-ILS showed a differentiation from HLSC profile and an endocrine commitment with the enhanced expression of several markers of β cell differentiation. The comparative analysis of gene expression profiles after 2 and 4 weeks of in vivo implantation showed a further β-cell differentiation, with a genetic profile still immature but closer to that of human islets. In conclusion, protamine-induced spheroid aggregation of HLSC triggers a spontaneous differentiation to an endocrine phenotype. Although the in vitro differentiated HLSC-ILS were immature, they responded to high glucose with insulin secretion and in vivo reversed hyperglycemia in diabetic SCID mice.

Original languageEnglish (US)
Pages (from-to)93-111
Number of pages19
JournalStem Cell Reviews and Reports
Volume15
Issue number1
DOIs
StatePublished - Feb 15 2019

Keywords

  • 3D culture
  • Diabetes
  • Insulin-producing stem cells
  • Liver stem cells
  • Pancreatic islets
  • Pancreatic β cells

ASJC Scopus subject areas

  • Cell Biology
  • Cancer Research

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