Connective tissue growth factor modulates adult β-cell maturity and proliferation to promote β-cell regeneration in mice.
Stimulation of endogenous β-cell expansion could facilitate regeneration in patients with diabetes. In mice, connective tissue growth factor (CTGF) is expressed in embryonic β-cells and in adult β-cells during periods of expansion. We discovered that in embryos CTGF is necessary for β-cell proliferation, and increased CTGF in β-cells promotes proliferation of immature (MafA(-)) insulin-positive cells. CTGF overexpression, under nonstimulatory conditions, does not increase adult β-cell proliferation. In this study, we tested the ability of CTGF to promote β-cell proliferation and regeneration after partial β-cell destruction. β-Cell mass reaches 50% recovery after 4 weeks of CTGF treatment, primarily via increased β-cell proliferation, which is enhanced as early as 2 days of treatment. CTGF treatment increases the number of immature β-cells but promotes proliferation of both mature and immature β-cells. A shortened β-cell replication refractory period is also observed. CTGF treatment upregulates positive cell-cycle regulators and factors involved in β-cell proliferation, including hepatocyte growth factor, serotonin synthesis, and integrin β1. Ex vivo treatment of whole islets with recombinant human CTGF induces β-cell replication and gene expression changes consistent with those observed in vivo, demonstrating that CTGF acts directly on islets to promote β-cell replication. Thus, CTGF can induce replication of adult mouse β-cells given a permissive microenvironment.
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN.
Kimberly G
KG
Riley
Department of Medicine, Vanderbilt University, Nashville, TN.
Raymond C
RC
Pasek
Department of Medicine, Vanderbilt University, Nashville, TN.
Matthew F
MF
Maulis
The School for Science and Math at Vanderbilt, Vanderbilt University, Nashville, TN.
Jennifer
J
Peek
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
Fabrizio
F
Thorel
Center for Cell and Vascular Biology, Children's Research Institute, The Ohio State University, Columbus, OH.
David R
DR
Brigstock
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland.
Pedro L
PL
Herrera
Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN Department of Medicine, Vanderbilt University, Nashville, TN Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN maureen.gannon@vanderbilt.edu.
Maureen
M
Gannon
D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D055513:Connective Tissue Growth Factor / Q000494:pharmacology*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D019012:Integrin beta1 / Q000378:metabolism; D051379:Mice; D012038:Regeneration / Q000187:drug effects*
D015820:Cadherins; D019012:Integrin beta1; D055513:Connective Tissue Growth Factor; D017228:Hepatocyte Growth Factor