New expansion technique improves supply of pancreatic progenitor cells

In a pioneering development for regenerative medicine, researchers at the Paul Langerhans Institute in Dresden identified the mechanisms that regulate the expansion and differentiation of pancreatic progenitor (PP) cells. This allowed the unlimited expansion of PP cells derived from human pluripotent stem (hPS) cells. The results of this work have now been published in "Elife".

Diabetes mellitus, which affects almost 10% of the world's population, occurs in two main forms, caused by the immunological destruction (type 1) or malfunction (type 2) of the insulin-producing beta cells in the islets of Langerhans in the pancreas. In severe cases, transplantation of the entire pancreas or islet cells is often required, but this is challenging due to the scarcity of donors and the need for lifelong immunosuppression. Therefore, much work has focused on harnessing the potential of hPS cells to generate pancreatic islet cells, known as SC-islets, which could provide an unlimited source of beta cells for transplantation. Now, Prof. Anthony Gavalas' group at the Paul Langerhans Institute in Dresden has made remarkable progress in the expansion of hPS cell derived PP cells, a crucial step for the clinical application of SC-islets in diabetes cell therapy.

According to their recently published results, the main challenge of their work was to maintain the self-renewal of PP cells while inhibiting their differentiation. The group identified specific conditions that allowed a 2000-fold expansion of PP cells over 10 passages and 40-45 days, providing a reproducible and GMP-compliant method. The chemically defined expansion medium decoupled PP proliferation from differentiation by stimulating specific mitogenic pathways while suppressing retinoic acid signalling and selected branches of the TGFβ and Wnt signalling. Besides promoting robust expansion of PP cells, the medium also promoted their efficient enrichment as shown by flow cytometry for PDX1⁺/SOX9⁺/NKX6-1⁺ PP cells. "This expansion procedure will facilitate the generation of SC-islets for further development, diabetes research, personalized medicine and cell therapies," comments Luka Jarc, the first author of the study, and continues: "The expanded PP cells showed efficiency and reproducibility in differentiating into SC-islets containing functional beta cells, as we demonstrated by glucose-stimulated insulin secretion assays."

Furthermore, the applicability of the method to different hPS cell lines and its compatibility with chemically defined culture media make it a versatile and scalable method for large-scale PP cell production. The researchers believe that this breakthrough will reduce variability in the differentiation process and facilitate the selection of optimally differentiated PP cell populations.

The researchers assume that the technology will play a decisive role in the further development of regenerative medicine under GMP (Good Manufacturing Practice) conditions. The availability of a high-purity, GMP-grade PP cell population derived from hPS cells is promising for future clinical applications and could make a significant contribution to overcoming the challenges of diabetes treatment. "The chemically defined expansion procedure we developed is an important step towards generating large numbers of human pancreatic endocrine cells of great interest for biomedical research and regenerative medicine," concluded Prof. Gavalas, highlighting the far-reaching implications of their important work.

This innovative approach is an important milestone in the search for scalable solutions for diabetes cell therapies and gives hope for better treatment options and advances in regenerative medicine. The group has a patent application for the method and a confidentiality agreement with Stem Cell Technologies to commercially develop this procedure.

Original Publication

Jarc L, Bandral M, Zanfrini E, Lesche M, Kufrin V, Sendra R, Pezzolla D, Giannios I, Khattak S, Neumann K, Ludwig B, Gavalas A. Regulation of multiple signaling pathways promotes the consistent expansion of human pancreatic progenitors in defined conditions. Elife. 2024 Jan 5;12:RP89962. doi: 10.7554/eLife.89962.