Endocrinol Metab.  2024 Apr;39(2):191-205. 10.3803/EnM.2023.1910.

Scaling Insulin-Producing Cells by Multiple Strategies

• Choi J
• Cayabyab F
• Perez H
• Yoshihara E

• KMID: 2554625
• DOI: http://doi.org/10.3803/EnM.2023.1910

Abstract

In the quest to combat insulin-dependent diabetes mellitus (IDDM), allogenic pancreatic islet cell therapy sourced from deceased donors represents a significant therapeutic advance. However, the applicability of this approach is hampered by donor scarcity and the demand for sustained immunosuppression. Human induced pluripotent stem cells are a game-changing resource for generating synthetic functional insulin-producing β cells. In addition, novel methodologies allow the direct expansion of pancreatic progenitors and mature β cells, thereby circumventing prolonged differentiation. Nevertheless, achieving practical reproducibility and scalability presents a substantial challenge for this technology. As these innovative approaches become more prominent, it is crucial to thoroughly evaluate existing expansion techniques with an emphasis on their optimization and scalability. This manuscript delineates these cutting-edge advancements, offers a critical analysis of the prevailing strategies, and underscores pivotal challenges, including cost-efficiency and logistical issues. Our insights provide a roadmap, elucidating both the promises and the imperatives in harnessing the potential of these cellular therapies for IDDM.

Keyword

Diabetes mellitus; Islet transplantation; Stem cells; Cell expansion; Mitogens; Cryopreservation

Figure

• 

  Fig. 1. Sources of human insulin-secreting β-like cells in sufficient numbers for transplantation into patients with diabetes. Over a long period of time, various methods have been studied to secure sufficient β-like cells that secrete human insulin for transplantation. Various approaches have been explored, including the method involves the expansion of stem cells over multiple passages to yield a substantial number of β-like cells. Additionally, direct strategies have been employed, such as using mitogens to stimulate human β cells’ entry into the cell cycle and the transdifferentiation of liver, gastric, intestinal, and other pancreatic cells such as α, δ, acinar, and ductal cells into β-like cells. Finally, Significant improvements have been made in the collection of high-quality islets from donors, as well as in the processes of cryopreservation and cell recovery for long-term storage and transportation. hPSC, human pluripotent stem cell; LN2, liquid nitrogen.

• 

  Fig. 2. Updated methodologies for β-like cell expansion at each step during stem cell-derived β cell differentiation. To date, methodologies have been reported for cell expansion at each stage of human pancreatic stem cell (hPSC)-derived β-like cell differentiation using optimized culture media. These methods report that cells retain their identity and capacity to differentiate through multiple passages. Exceptionally, a methodology to expand endocrine progenitor (EP) cells has not been reported. The Hippo signaling pathway is essential for regulating pancreatic development, as well as β cell proliferation, differentiation and survival. Overexpression of YAP-S6A in pancreatic progenitor cells reduces the differentiation efficiency into β-like cells, but increases the number of proliferating β-like cells [26,93,99-102]. FGF10, fibroblast growth factor 10; EGF, epidermal growth factor; TGFβ, transforming growth factor β; Inh, inhibitor; P, passage; Ha, harmine; LY, LY364947; LIF, leukemia inhibitory factor; DE, definitive endoderm; FG, foregut; PP, pancreatic progenitor; TesR1, mTESR™1; BMP4, bone morphogenetic protein 4; bFGF, basic fibroblast growth factor; VEGF, vascular endothelial growth factor; MEF, mouse embryonic fibroblast; HGF, hepatocyte growth factor; OE, overexpression.

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