PAX4 Defines an Expandable β-Cell Subpopulation in the Adult Pancreatic Islet.
PAX4 is a key regulator of pancreatic islet development whilst in adult acute overexpression protects β-cells against stress-induced apoptosis and stimulates proliferation. Nonetheless, sustained PAX4 expression promotes β-cell dedifferentiation and hyperglycemia, mimicking β-cell failure in diabetic patients. Herein, we study mechanisms that allow stringent PAX4 regulation endowing favorable β-cell adaptation in response to changing environment without loss of identity. To this end, PAX4 expression was monitored using a mouse bearing the enhanced green fluorescent protein (GFP) and cre recombinase construct under the control of the islet specific pax4 promoter. GFP was detected in 30% of islet cells predominantly composed of PAX4-enriched β-cells that responded to glucose-induced insulin secretion. Lineage tracing demonstrated that all islet cells were derived from PAX4(+) progenitor cells but that GFP expression was confined to a subpopulation at birth which declined with age correlating with reduced replication. However, this GFP(+) subpopulation expanded during pregnancy, a state of active β-cell replication. Accordingly, enhanced proliferation was exclusively detected in GFP(+) cells consistent with cell cycle genes being stimulated in PAX4-overexpressing islets. Under stress conditions, GFP(+) cells were more resistant to apoptosis than their GFP(-) counterparts. Our data suggest PAX4 defines an expandable β-cell sub population within adult islets.
Pancreatic Islet Development and Regeneration Unit, Department of Stem Cells, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain.
Petra I
PI
Lorenzo
Pancreatic Islet Development and Regeneration Unit, Department of Stem Cells, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain.
Esther
E
Fuente-Martín
Department of Cell Physiology and Metabolism, University of Geneva, Geneva, Switzerland.
Thierry
T
Brun
Pancreatic Islet Development and Regeneration Unit, Department of Stem Cells, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain.
Nadia
N
Cobo-Vuilleumier
Pancreatic Islet Development and Regeneration Unit, Department of Stem Cells, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain.
Carmen María
CM
Jimenez-Moreno
Pancreatic Islet Development and Regeneration Unit, Department of Stem Cells, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain.
Irene
I
G Herrera Gomez
Pancreatic Islet Development and Regeneration Unit, Department of Stem Cells, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain.
Livia
L
López Noriega
Pancreatic Islet Development and Regeneration Unit, Department of Stem Cells, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain.
José Manuel
JM
Mellado-Gil
Pancreatic Islet Development and Regeneration Unit, Department of Stem Cells, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain.
Alejandro
A
Martin-Montalvo
Cellular Therapy of Diabetes Mellitus and its Complications, Department of Stem Cells, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain.|CIBERDEM, Instituto Carlos III, Madrid, Spain.
Bernat
B
Soria
Pancreatic Islet Development and Regeneration Unit, Department of Stem Cells, CABIMER-Andalusian Center for Molecular Biology and Regenerative Medicine, Seville, Spain.
Benoit R
BR
Gauthier
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D054337:Cell Dedifferentiation / Q000502:physiology; D019070:Cell Lineage; D049109:Cell Proliferation / Q000502:physiology; D003920:Diabetes Mellitus / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006943:Hyperglycemia / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000145:classification / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics
D018398:Homeodomain Proteins; D007328:Insulin; D051761:Paired Box Transcription Factors; C110218:Pax4 protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins