Methylcellulose colony assay and single-cell micro-manipulation reveal progenitor-like cells in adult human pancreatic ducts

Quijano, Janine C.; Wedeken, Lena; Ortíz, José Antonio; Zook, Heather N.; LeBon, Jeanne M.; Luo, Angela; Rawson, Jeffrey; Tremblay, Jacob R.; Mares, Jacob M.; Lopez, Kassandra; Chen, Min-Hsuan; Jou, Kevin; Mendez‐Dorantes, Carlos; Al-Abdullah, Ismail H.; Thurmond, Debbie C.; Kandeel, Fouad; Riggs, Arthur D.; Ku, Hsun Teresa

doi:10.1016/j.stemcr.2023.02.001

Cited by 4 publications

(4 citation statements)

References 51 publications

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“…We recently showed that human adult ductal progenitor-like cells can be differentiated into endocrine progenitor cells in vitro using a Notch signaling inhibitor, and these endocrine progenitor cells subsequently give rise to insulin expressing cells that function in transplanted insulin-dependent diabetic mice. 20 Together, these results implicate adult ductal progenitor-like cells as potential targets for beta cell neogenesis and regenerative medicine in diabetes.…”

Section: Discussionmentioning

confidence: 89%

“…We recently reported the existence of SOX9 + /PDX1 + /NKX6-1 + progenitor cells in the endogenous ducts of normal adult human pancreas. 20 The TP cells are a feature of embryonic MPCs 32 , 33 but have been unknown in the adult pancreas. In addition, adult ductal clusters express many other known embryonic MPC genes, such as Hnf1b, Hes1, Foxa2, Tead1, Nkx2-2, Rbpj, Glis3, Nr5a2, Gata6, Yap1, Taz , and Myc 47 ; interestingly, Ptf1a and Gata4 are absent ( Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

“… 23 , 24 These in vivo results are also supported by the demonstration of in vitro self-renewal and endocrine differentiation of some ductal cells from adult pancreas, which used fluorescence-activated cell sorting (FACS) to enrich progenitor-like cells from mice 25-28 or humans. 20 , 29 , 30 We have previously shown that the sorted CD133 high CD71 low ductal cells from normal adult mice are a subpopulation of total ductal cells, and are enriched for progenitor-like cells that both self-renew and give rise to the three main pancreatic lineages, as assayed by a unique, 3D colony assay system permissive for tri-lineage differentiation. 31 However, purification of these progenitor-like cells has not been achieved.…”

Section: Introductionmentioning

confidence: 99%

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Rare, Tightly-Bound, Multi-Cellular Clusters in the Pancreatic Ducts of Adult Mice Function Like Progenitor Cells and Survive and Proliferate After Acinar Cell Injury

Tremblay,

Ortiz,

Quijano

et al. 2024

Stem Cells

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Pancreatic ductal progenitor cells have been proposed to contribute to adult tissue maintenance and regeneration after injury, but the identity of such ductal cells remains elusive. Here, from adult mice, we identify a near homogenous population of ductal progenitor-like clusters, with an average of 8 cells per cluster. They are a rare subpopulation, about 0.1% of the total pancreatic cells, and can be sorted using a fluorescence-activated cell sorter with the CD133highCD71lowFSCmid-high phenotype. They exhibit properties in self-renewal and tri-lineage differentiation (including endocrine-like cells) in a unique 3-dimensional colony assay system. An in vitro lineage tracing experiment, using a novel HprtDsRed/+ mouse model, demonstrates that a single cell from a cluster clonally gives rise to a colony. Droplet RNAseq analysis demonstrates that these ductal clusters express embryonic multipotent progenitor cell markers Sox9, Pdx1, and Nkx6-1, and genes involved in actin cytoskeleton regulation, inflammation responses, organ development and cancer. Surprisingly, these ductal clusters resist prolonged trypsin digestion in vitro, preferentially survive in vivo after a severe acinar cell injury and become proliferative within 14 days post-injury. Thus, the ductal clusters are the fundamental units of progenitor-like cells in the adult murine pancreas with implications in diabetes treatment and tumorigenicity.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rare, Tightly-Bound, Multi-Cellular Clusters in the Pancreatic Ducts of Adult Mice Function Like Progenitor Cells and Survive and Proliferate After Acinar Cell Injury

Tremblay,

Ortiz,

Quijano

et al. 2024

Stem Cells

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“…[ 15 ] As development proceeds, HES1 repression allows cells to differentiate toward the pancreatic endocrine cell fate, whereas PPs maintain the progenitor state and direct cells toward a pancreatic ductal fate by maintaining SOX9 expression. [ 16 ]…”

Section: Introductionmentioning

confidence: 99%

LINC MIR503HG Controls SC‐β Cell Differentiation and Insulin Production by Targeting CDH1 and HES1

Xu,

Mao,

Fan

et al. 2024

Advanced Science

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Stem cell‐derived pancreatic progenitors (SC‐PPs), as an unlimited source of SC‐derived β (SC‐β) cells, offers a robust tool for diabetes treatment in stem cell‐based transplantation, disease modeling, and drug screening. Whereas, PDX1+/NKX6.1+ PPs enhances the subsequent endocrine lineage specification and gives rise to glucose‐responsive SC‐β cells in vivo and in vitro. To identify the regulators that promote induction efficiency and cellular function maturation, single‐cell RNA‐sequencing is performed to decipher the transcriptional landscape during PPs differentiation. The comprehensive evaluation of functionality demonstrated that manipulating LINC MIR503HG using CRISPR in PP cell fate decision can improve insulin synthesis and secretion in mature SC‐β cells, without effects on liver lineage specification. Importantly, transplantation of MIR503HG−/− SC‐β cells in recipients significantly restored blood glucose homeostasis, accompanied by serum C‐peptide release and an increase in body weight. Mechanistically, by releasing CtBP1 occupying the CDH1 and HES1 promoters, the decrease in MIR503HG expression levels provided an excellent extracellular niche and appropriate Notch signaling activation for PPs following differentiation. Furthermore, this exhibited higher crucial transcription factors and mature epithelial markers in CDH1High expressed clusters. Altogether, these findings highlighted MIR503HG as an essential and exclusive PP cell fate specification regulator with promising therapeutic potential for patients with diabetes.

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Activation of ductal progenitor-like cells from adult human pancreas requires extracellular matrix protein signaling

Zook,

Quijano,

Ortiz

et al. 2024

iScience

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Methylcellulose colony assay and single-cell micro-manipulation reveal progenitor-like cells in adult human pancreatic ducts

Cited by 4 publications

References 51 publications

Rare, Tightly-Bound, Multi-Cellular Clusters in the Pancreatic Ducts of Adult Mice Function Like Progenitor Cells and Survive and Proliferate After Acinar Cell Injury

Rare, Tightly-Bound, Multi-Cellular Clusters in the Pancreatic Ducts of Adult Mice Function Like Progenitor Cells and Survive and Proliferate After Acinar Cell Injury

LINC MIR503HG Controls SC‐β Cell Differentiation and Insulin Production by Targeting CDH1 and HES1

Activation of ductal progenitor-like cells from adult human pancreas requires extracellular matrix protein signaling

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