Pancreatic endocrine progenitor cells and uses thereof
A technique for endocrine progenitor cells and pancreatic islet cells, which is applied to the field of pancreatic endocrine progenitor cells and their uses, and can solve the problems of producing beta cells and the like
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Embodiment 1
[0115] Example 1: From Resident Procr + Long-term expansion of islet organoids with progenitor cells
[0116] Procr in adult islets + progenitor cell population
[0117] Since Procr is a surface protein, it has been reported to label stem cells in several adult tissues, including mammary glands (Wang et al., 2015), endothelial cells (Yu et al., 2016), and the hematopoietic system (Balazs et al., 2006; Fares et al., 2017; Iwasaki et al., 2010; Zhou et al., 2016), we used single-cell (sc) RNA sequencing to search for Procr-positive cells in mouse islets. Pancreata from 8-week-old adult mice were isolated and enriched for endocrine cells (see Methods section below). 7,160 cells were analyzed using single-cell RNA sequencing ( Figures 1A-1D ). Each cluster was mapped to known abundant endocrine (alpha, beta-, delta, and PP cells), abundant exocrine (acinar and ductal cells), or rare (mesenchymal, endothelial, immune, and stellate) cells type( Figure 1D-1G ). A single clu...
Embodiment 2
[0184] Example 2: Long-Term Culture and Expansion of Human Islet Organoids
[0185] Transplantation of islets from cadaveric organ donation and whole pancreas provides proof-of-concept for the restoration of glucose homeostasis following replenishment of disease-causing beta-cell deficiency (Lysy et al., 2013). The scarcity of donors has led to the search for strategies to generate beta cells in vitro. Making new beta-cells in vitro has proven challenging. Cell therapy for diabetes requires identification of candidate cell sources and new culture strategies. Our previous studies in murine pancreas (see Example 1) identified a new population of endocrine progenitor cells. These cells do not express markers of pancreatic differentiation and can be sorted from islets based on the expression of the surface protein C receptor (Procr). These cells can form islet-like organoids in culture, respond to glucose, secrete insulin, and can expand long-term. In the current study, we exp...
Embodiment 3
[0210] Example 3: Identification of human adult pancreatic endocrine / islet progenitor cells and in vitro culture into islet organoids
[0211] To identify potential human endocrine progenitor populations, we performed scRNA-seq using isolated pancreatic cells from 2 donors. They were combined with published human pancreas datasets (Baron et al., 2016; Enge et al., 2017; Grün et al., 2016; Lawlor et al., 2017; Muraro et al., 2016; Segerstolpe et al., 2016) and with published mouse Pancreatic dataset integration ((Wang et al., 2020), also in Example 1). A total of 20,660 human cells (8 datasets) and 7,051 mouse cells (3 datasets) were analyzed ( Figures 14A-14B ). Each cluster was mapped to known abundant endocrine (alpha, beta, delta, epsilon, and PP cells), abundant exocrine (acinar and ductal cells), or rare (endothelial, immune, dormant, and active stellate) cells type( Figures 14A-14C ). An integrative approach reveals a potential endocrine progenitor cluster in huma...
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