In the setting of β-cell stress, the pancreatic duct gland transcriptome shows characteristics of an activated regenerative response

Butler, Alexandra E.; Kirakossian, David; Gurlo, Tatyana; Gao, Fuying; Coppola, Giovanni; Butler, Peter C.

doi:10.1152/ajpgi.00177.2018

Cited by 4 publications

(7 citation statements)

References 23 publications

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“…S3). The presence of Mucin 20 among the DE genes further confirms the potential link of these cells to PDGs, which have long been proposed to be niches of pancreatic progenitors (24)(25)(26)(27).…”

Section: Resultssupporting

confidence: 56%

Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche

Qadir

Álvarez-Cubela

Klein

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

144

134

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We have described multipotent progenitor-like cells within the major pancreatic ducts (MPDs) of the human pancreas. They express PDX1, its surrogate surface marker P2RY1, and the bone morphogenetic protein (BMP) receptor 1A (BMPR1A)/activin-like kinase 3 (ALK3), but not carbonic anhydrase II (CAII). Here we report the single-cell RNA sequencing (scRNA-seq) of ALK3bright+-sorted ductal cells, a fraction that harbors BMP-responsive progenitor-like cells. Our analysis unveiled the existence of multiple subpopulations along two major axes, one that encompasses a gradient of ductal cell differentiation stages, and another featuring cells with transitional phenotypes toward acinar tissue. A third potential ducto-endocrine axis is revealed upon integration of the ALK3bright+ dataset with a single-cell whole-pancreas transcriptome. When transplanted into immunodeficient mice, P2RY1+/ALK3bright+ populations (enriched in PDX1+/ALK3+/CAII− cells) differentiate into all pancreatic lineages, including functional β-cells. This process is accelerated when hosts are treated systemically with an ALK3 agonist. We found PDX1+/ALK3+/CAII− progenitor-like cells in the MPDs of types 1 and 2 diabetes donors, regardless of the duration of the disease. Our findings open the door to the pharmacological activation of progenitor cells in situ.

show abstract

Section: Resultssupporting

confidence: 56%

Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche

Qadir

Álvarez-Cubela

Klein

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

144

134

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“…28 Migration is a basic cellular function that is involved in physiological and pathological behaviors such as tumor cell proliferation, embryo development, and wound healing. 29,30 We showed here that MT1JP overexpression significantly inhibited the proliferation and migration of liver cancer cells, increased apoptosis rates, downregulated the expression of Bcl-2 and migration-related proteins MMP-2 and MMP-9, and upregulated that of the apoptosis-related proteins Bax, Caspase-3, and Caspase-9. These findings suggest that MT1JP could inhibit tumors and therefore serve as a therapeutic target for liver cancer.…”

Section: Discussionmentioning

confidence: 78%

<p>Overexpression of lncRNA MT1JP Mediates Apoptosis and Migration of Hepatocellular Carcinoma Cells by Regulating miR-24-3p</p>

Shan

Chen

Meng

et al. 2020

CMAR

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Objective: This study aimed to determine the effects of the long non-coding (lnc) RNA MT1JP on the apoptosis and migration of hepatocellular carcinoma cells. Patients and Methods: Patients with liver cancer admitted to the Second People's Hospital of Liaocheng were included in this study. We transfected hepatocellular carcinoma cells with MT1JP and miR-24-3p and assessed their expression and effects on apoptosis and migration. Correlations were verified using a dual-luciferase reporter and RNA-binding protein coimmunoprecipitation.Results: The expression of MT1JP was downregulated (P < 0.05), whereas that of miR-24-3p was upregulated in liver cancer. Serum MT1JP levels were correlated with tumor size, alpha-fetoprotein (AFP), TNM stage, differentiation, and lymph node metastasis. Both MT1JP overexpression and miR-24-3p inhibition inhibited cellular proliferation and migration and increased apoptosis rates. They significantly downregulated expression of the cell migration-associated proteins matrix metalloproteinase -2, -9 (MMP-2, MMP-9) (P < 0.05). They upregulated the expression of Bcl-2-related X protein (Bax) and cysteinyl aspartatespecific proteinases (Caspase-3 and -9) proteins that are involved in apoptosis. They decreased expression of B-cell lymphoma/leukemia-2 (Bcl-2; P < 0.05). A target relationship between MT1JP and miR-24-3p was identified using dual-luciferase gene reporter assays and RNA-binding protein coimmunoprecipitations. MT1JP overexpression significantly downregulated miR-24-3p expression (P < 0.05). MT1JP and miR-24-3p expression were negatively correlated in liver cancer tissues (r = −0.561, P < 0.001; Pearson χ 2 tests). Rescue experiments showed that upregulating miR-24-3p expression could counteract MT1JP overexpression in hepatocellular carcinoma cells. Conclusion: MT1JP, even when expressed at low levels, participates in the proliferation, apoptosis, and migration of liver cancer cells by regulating miR-24-3p.

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“…19 PDGs are anatomically similar to PBGs, [16][17][18][19] for pancreatic ductal epithelial repair and regeneration. [15][16][17][18][19][20] Cells of the human PDG are also mucin producing, 16,19,20 with intense PAS cytoplasmic staining. Though, these regions observed in the porcine CL and DL share a similar phenotype, it is unclear if they are identical to human PDGs.…”

Section: Discussionmentioning

confidence: 99%

“…The phenotype of these regions resembles PDGs associated with the pancreatic duct system in the human and mouse pancreas. [15][16][17][18][19][20]…”

Section: Cellular Composition and Phenotypical Differences Between Pa...mentioning

confidence: 99%

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Heterogenous expression of endocrine and progenitor cells within the neonatal porcine pancreatic lobes–Implications for neonatal porcine islet xenotransplantation

Seeberger

Salama

Kelly

et al. 2023

Xenotransplantation

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Neonatal porcine islets (NPIs) are a source of islets for xenotransplantation. In the pig, the pancreatic lobes remain separate, thus, when optimizing NPI isolation, the pancreatic lobes included in the pancreatic digest should be specified. These lobes are the duodenal (DL), splenic (SL) and connecting (CL) lobe that correspond to the head, body‐tail, and uncinate process of the human pancreas. In this study we are the first to evaluate all three neonatal porcine pancreatic lobes and NPIs isolated from these lobes. We report, a significant difference in endocrine and progenitor cell composition between lobes, and observed pancreatic duct glands (PDG) within the mesenchyme surrounding exocrine ducts in the DL and CL. Following in vitro differentiation, NPIs isolated from each lobe differed significantly in the percent increase of endocrine cells and final cell composition. Compared to other recipients, diabetic immunodeficient mice transplanted with NPIs isolated from the SL demonstrated euglycemic control as early as 4 weeks (p < 0.05) and achieved normoglycemia by 6 weeks post‐transplant (p < 0.01). For the first time we report significant differences between the neonatal porcine pancreatic lobes and demonstrate that NPIs from these lobes differ in xenograft function.

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In the setting of β-cell stress, the pancreatic duct gland transcriptome shows characteristics of an activated regenerative response

Cited by 4 publications

References 23 publications

Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche

Single-cell resolution analysis of the human pancreatic ductal progenitor cell niche

<p>Overexpression of lncRNA MT1JP Mediates Apoptosis and Migration of Hepatocellular Carcinoma Cells by Regulating miR-24-3p</p>

Heterogenous expression of endocrine and progenitor cells within the neonatal porcine pancreatic lobes–Implications for neonatal porcine islet xenotransplantation

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