Pancreatic Progenitor Commitment Is Marked by an Increase in Ink4a/Arf Expression

Biomolecules. 2021 Jul 30;11(8):1124. doi: 10.3390/biom11081124.


The identification of the molecular mechanisms controlling early cell fate decisions in mammals is of paramount importance as the ability to determine specific lineage differentiation represents a significant opportunity for new therapies. Pancreatic Progenitor Cells (PPCs) constitute a regenerative reserve essential for the maintenance and regeneration of the pancreas. Besides, PPCs represent an excellent model for understanding pathological pancreatic cellular remodeling. Given the lack of valid markers of early endoderm, the identification of new ones is of fundamental importance. Both products of the Ink4a/Arf locus, in addition to being critical cell-cycle regulators, appear to be involved in several disease pathologies. Moreover, the locus' expression is epigenetically regulated in ES reprogramming processes, thus constituting the ideal candidates to modulate PPCs homeostasis. In this study, starting from mouse embryonic stem cells (mESCs), we analyzed the early stages of pancreatic commitment. By inducing mESCs commitment to the pancreatic lineage, we observed that both products of the Cdkn2a locus, Ink4a and Arf, mark a naïve pancreatic cellular state that resembled PPC-like specification. Treatment with epi-drugs suggests a role for chromatin remodeling in the CDKN2a (Cycline Dependent Kinase Inhibitor 2A) locus regulation in line with previous observations in other cellular systems. Our data considerably improve the comprehension of pancreatic cellular ontogeny, which could be critical for implementing pluripotent stem cells programming and reprogramming toward pancreatic lineage commitment.

Keywords: ARF; Cdkn2a; INK4a; Pancreatic Progenitor Cells; embryonic stem cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cell Differentiation
  • Cell Lineage / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Epigenesis, Genetic*
  • Gene Expression*
  • Genetic Loci
  • Hepatocyte Nuclear Factor 3-beta / genetics
  • Hepatocyte Nuclear Factor 3-beta / metabolism
  • Hepatocyte Nuclear Factor 6 / genetics
  • Hepatocyte Nuclear Factor 6 / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / metabolism*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Mice
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism*
  • Nanog Homeobox Protein / genetics
  • Nanog Homeobox Protein / metabolism
  • Octamer Transcription Factor-3 / genetics
  • Octamer Transcription Factor-3 / metabolism
  • Pancreas / cytology
  • Pancreas / metabolism
  • Primary Cell Culture
  • Trans-Activators / genetics
  • Trans-Activators / metabolism


  • Biomarkers
  • Cyclin-Dependent Kinase Inhibitor p16
  • Foxa2 protein, mouse
  • Hepatocyte Nuclear Factor 6
  • Homeodomain Proteins
  • Intercellular Signaling Peptides and Proteins
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • Nkx6-1 protein, mouse
  • Octamer Transcription Factor-3
  • Onecut1 protein, mouse
  • Pou5f1 protein, mouse
  • Trans-Activators
  • nephrocan protein, mouse
  • pancreatic and duodenal homeobox 1 protein
  • Hepatocyte Nuclear Factor 3-beta