Expansion of Adult Human Pancreatic Tissue Yields Organoids Harboring Progenitor Cells with Endocrine Differentiation Potential

Summary

Generating an unlimited source of human insulin-producing cells is a prerequisite to advance β cell replacement therapy for diabetes. Here, we describe a 3D culture system that supports the expansion of adult human pancreatic tissue and the generation of a cell subpopulation with progenitor characteristics. These cells display high aldehyde dehydrogenase activity (ALDH ^hi), express pancreatic progenitors markers ( PDX1, PTF1A, CPA1, and MYC), and can form new organoids in contrast to ALDH ^lo cells. Interestingly, gene expression profiling revealed that ALDH ^hi cells are closer to human fetal pancreatic tissue compared with adult pancreatic tissue. Endocrine lineage markers were detected upon in vitro differentiation. Engrafted organoids differentiated toward insulin-positive (INS ⁺) cells, and circulating human C-peptide was detected upon glucose challenge 1 month after transplantation. Engrafted ALDH ^hi cells formed INS ⁺ cells. We conclude that adult human pancreatic tissue has potential for expansion into 3D structures harboring progenitor cells with endocrine differentiation potential.

Highlights

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  A 3D culture system can support the expansion of adult human pancreatic tissue

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  An ALDH ^hi cell subpopulation is identified in these organoids

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  ALDH ^hi cells, and not ALDH ^lo cells, are capable of forming new organoids

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  ALDH ^hi cells show endocrine differentiation potential

Abstract

In the context of β cell replacement therapy for diabetes, de Koning and colleagues describe a 3D culture platform that supports ex vivo expansion of human pancreatic tissue as organoids. These organoids harbor a subpopulation of ALDH ^hi cells that display proliferative capacity and can differentiate to an endocrine fate.