Int J Stem Cells.  2024 Aug;17(3):253-269. 10.15283/ijsc24036.

Pancreatic Diseases: Genetics and Modeling Using Human Pluripotent Stem Cells

• Lee Y
• Lee K

• KMID: 2558604
• DOI: http://doi.org/10.15283/ijsc24036

Abstract

Pancreas serves endocrine and exocrine functions in the body; thus, their pathology can cause a broad range of irreparable consequences. Endocrine functions include the production of hormones such as insulin and glucagon, while exocrine functions involve the secretion of digestive enzymes. Disruption of these functions can lead to conditions like diabetes mellitus and exocrine pancreatic insufficiency. Also, the symptoms and causality of pancreatic cancer very greatly depends on their origin: pancreatic ductal adenocarcinoma is one of the most fatal cancer; however, most of tumor derived from endocrine part of pancreas are benign. Pancreatitis, an inflammation of the pancreatic tissues, is caused by excessive alcohol consumption, the bile duct obstruction by gallstones, and the premature activation of digestive enzymes in the pancreas. Hereditary pancreatic diseases, such as maturity-onset diabetes of the young and hereditary pancreatitis, can be a candidate for disease modeling using human pluripotent stem cells (hPSCs), due to their strong genetic influence. hPSC-derived pancreatic differentiation has been established for cell replacement therapy for diabetic patients and is robustly used for disease modeling. The disease modeling platform that allows interactions between immune cells and pancreatic cells is necessary to perform in-depth investigation of disease pathogenesis.

Keyword

Pancreatic diseases; Diabetes mellitus; Pancreatic neoplasms; Pancreatitis; Pluripotent stem cells

Figure

• 

  Fig. 1 The role and anatomy of the pancreas. (A) The anatomy of the pancreas is shown. The endocrine part is composed of α-cells, β-cells, γ-cells, δ-cells, and ε-cells. The exocrine part is composed of ductal cells, which produce bicarbonate (HCO3−) and acinar cells, which produce lipase, amylase, and protease. The bile duct joins the main pancreatic duct before it is connected with the duodenum at the ampulla of Vater. (B) In a healthy pancreas, the activation of trypsinogen only occurs by the serine protease enterokinase in the duodenum, which is the first part of small intestine. This protects the pancreatic tissues from protease digestion. In acute pancreatitis, trypsin can autoactivate trypsinogen in the pancreas and this abnormal intrapancreatic trypsin activity results in damage to pancreatic acinar cells, triggering inflammation. Recurrent acute pancreatitis can cause necrosis and fibrosis of pancreas leading permanent deformation. (C) The protein structure of the human trypsinogen is shown. The sequences of NP_002760.1 was visualized using the PROTTER (https://wlab.ethz.ch/protter). Cleavage of trypsinogen can cause its autoactivation or degradation, depending on the cleavage site. Autoactivation occurs when the Phe18-Asp19 peptide bond is cleaved by chymotrypsin C (CTRC) and the Lys23-Ile24 peptide bond is cleaved by trypsin. Degradation is caused when the Leu81-Glu82 peptide bond is cleaved by CTRC and the Arg122-Val123 peptide bond is cleaved by trypsin.

• 

  Fig. 2 Hereditary pancreatic diseases-associated genetic variants. All variants, which are classified as pathogenic or likely pathogenic for each gene, HNF4A (MODY1) (A), GCK (MODY2) (B), PDX1 (MODY4) (C), HNF1B (MODY5) (D), PRSS1 (E), SPINK1 (F), CTRC (G), and CPA1 (H), are selected from on the ClinVar (https://www.ncbi.nlm.nih.gov/clinvar). Detailed information of variants is available in Table 2. The variants are annotated where exons are shown as boxes and intros are depicted as lines. The consequence of variants also demonstrated at the protein level. The pathogenic variants are indicated in red, while likely pathogenic variants are highlighted in orange, and those classified as pathogenic/likely pathogenic, or conflicting are marked in black.

• 

  Fig. 3 Pancreatic development and human stem cell-derived differentiation. (A) Development of pancreas. The scheme is modified from Jin and Jiang (1). Epiblast gives rise to three germ layers including ectoderm, mesoderm, and endoderm. The definitive endoderm (DE) then develops into the primitive gut tube (PGT), which is sometimes referred to as the gut tube endoderm (GTE). PGT subsequently differentiates into the foregut, midgut, and hindgut. Pancreatic progenitor (PP) cells emerge from the posterior region of the foregut. These PP cells form dorsal and ventral pancreatic buds that eventually merge, creating a multi-layered epithelial system with a lumen. The pancreatic epithelium undergoes expansion and branching, giving rise to the tip domain and trunk domain. The tip domain, which expresses the transcription factor PTF1A, differentiates into acinar progenitors, while the trunk domain, which expresses NKX6-1, gives rise to endocrine and ductal progenitors. The appropriate pancreatic cell types can be obtained through the directed expression of additional lineage-specific transcription factors in the PP cells. The pancreatic differentiation from human pluripotent stem cells (hPSCs) has established to mimic in vivo development by coordinating the timing of the activation or inhibition of signaling pathways using a variety of growth factors and small molecules. (B) Endocrine differentiation from hPSCs. Compounds and growth factors required for pancreatic endocrine differentiation from hPSCs are summarized. hESC: human embryonic stem cell, PFG: posterior foregut, PEC: pancreatic endocrine cells, EN: endocrine cell, SC-β cells: stem cell-derived pancreatic β-cells, EP: endocrine precursor, IHI: immature hPSC-islets, MHI: maturing hPSC-islets, Activin A: transforming growth factor (TGF)-β family member, BMP, bone morphogenetic protein, CHIR: CHIR99021, WNT activator, RA: retinoic acid, LDN: LDN193189, BMP pathway inhibitor, SANT1: hedgehog inhibitor, PDbU: phorbol 12,13-dibutyrate, protein kinase C activator, TPPB: protein kinase C activator, XXI: γ-secretase inhibitor, Notch inhibitor, T3: L-3,3’,5-triiodothyronine, LatA: Latrunculin A, Betacellulin: EGF family, actin depolymerizer, ALK5i: ALK5 inhibitor, LAA: L-ascorbic acid, NAC: N-acetyl cysteine, GSI XX: γ-secretase inhibitor, Trolox: vitamin E analog, R428: AXL inhibitor, GDF-8: growth differentiation factor-8, TGF-β family member, MCX-928: WNT activator. (C) Exocrine differentiation from hPSCs. Compounds and growth factors required for pancreatic exocrine differentiation from hPSCs are summarized. PE: pancreatic endoderm, PDEC: pancreatic ductal epithelial cell, PTrLO: pancreatic trunk-like organoids, PDLO: pancreatic duct-like organoids, PO: pancreatic organoids, DO: ductal organoids, AO: acinar organoids, VPA: valproic acid, Dorsomorphin: BMP inhibitor, PD0325901: MEK/ERK pathway inhibitor, SB431542: TGF-β inhibitor, A83-01: TGF-β receptor inhibitor, SKL2001:Wnt agonist, Foxy5: WNT5A agonist, DBZ: γ-secretase inhibitor, HPI 1: hedgehog inhibitors, XMU-MP-1: MST1/2 inhibitor, IQ1: Wnt inhibitor, iCRT-14: Wnt inhibitor, CPTH2: histone acetyltransferase inhibitor, SB939: pracinostat, pan-HDAC inhibitor, WT161: HDAC6 inhibitor, XAV939: Wnt inhibitor, EPZ011989: histone methyltransferase inhibitor.

Reference

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