Macrophages are essential for CTGF-mediated adult β-cell proliferation after injury.
OBJECTIVE
Promotion of endogenous β-cell mass expansion could facilitate regeneration in patients with diabetes. We discovered that the secreted protein CTGF (aka CCN2) promotes adult β-cell replication and mass regeneration after injury via increasing β-cell immaturity and shortening the replicative refractory period. However, the mechanism of CTGF-mediated β-cell proliferation is unknown. Here we focused on whether CTGF alters cells of the immune system to enhance β-cell replication.


METHODS
Using mouse models for 50% β-cell ablation and conditional, β-cell-specific CTGF induction, we assessed changes in immune cell populations by performing immunolabeling and gene expression analyses. We tested the requirement for macrophages in CTGF-mediated β-cell proliferation via clodronate-based macrophage depletion.


RESULTS
CTGF induction after 50% β-cell ablation increased both macrophages and T-cells in islets. An upregulation in the expression of several macrophage and T-cell chemoattractant genes was also observed in islets. Gene expression analyses suggest an increase in M1 and a decrease in M2 macrophage markers. Depletion of macrophages (without changes in T cell number) blocked CTGF-mediated β-cell proliferation and prevented the increase in β-cell immaturity.


CONCLUSIONS
Our data show that macrophages are critical for CTGF-mediated adult β-cell proliferation in the setting of partial β-cell ablation. This is the first study to link a specific β-cell proliferative factor with immune-mediated β-cell proliferation in a β-cell injury model.
Department of Cell and Developmental Biology at Vanderbilt University, Nashville, TN, USA.
Kimberly G
KG
Riley
Department of Medicine at Vanderbilt University, Nashville, TN, USA.
Raymond C
RC
Pasek
Department of Medicine at Vanderbilt University, Nashville, TN, USA.
Matthew F
MF
Maulis
Department of Medicine at Vanderbilt University, Nashville, TN, USA.
Jennifer C
JC
Dunn
Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN, USA ; Departments of Molecular Physiology and Biophysics at Vanderbilt University, Nashville, TN, USA.
W Reid
WR
Bolus
Department of Medicine at Vanderbilt University, Nashville, TN, USA.
Peggy L
PL
Kendall
Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN, USA ; Departments of Molecular Physiology and Biophysics at Vanderbilt University, Nashville, TN, USA.
Alyssa H
AH
Hasty
Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN, USA ; Department of Cell and Developmental Biology at Vanderbilt University, Nashville, TN, USA ; Department of Medicine at Vanderbilt University, Nashville, TN, USA ; Departments of Molecular Physiology and Biophysics at Vanderbilt University, Nashville, TN, USA.
Maureen
M
Gannon
CTGF; Macrophages; Proliferation; Regeneration; T-cells; β-cell