Abstract
Damaged acinar cells play a passive role in activating pancreatic stellate cells (PSCs) via recruitment of immune cells that subsequently activate PSCs. However, whether acinar cells directly contribute to PSC activation is unknown. Here, we report that the Hippo pathway, a well-known regulator of proliferation, is essential for suppression of expression of inflammation and fibrosis-associated genes in adult pancreatic acinar cells. Hippo inactivation in acinar cells induced yes-associated protein 1 (YAP1)/transcriptional coactivator with PDZ binding motif (TAZ)-dependent, irreversible fibrosis and inflammation, which was initiated by Hippo-mediated acinar-stromal communications and ameliorated by blocking YAP1/TAZ target connective tissue growth factor (CTGF). Hippo disruption promotes acinar cells to secrete fibroinflammatory factors and induce stromal activation, which precedes acinar proliferation and metaplasia. We found that Hippo disruption did not induce cell-autonomous proliferation but primed acinar cells to exogenous pro-proliferative stimuli, implying a well-orchestrated scenario in which Hippo signaling acts as an intrinsic link to coordinate fibroinflammatory response and proliferation for maintenance of the tissue integrity. Our findings suggest that the fibroinflammatory program in pancreatic acinar cells is suppressed under normal physiological conditions. While transient activation of inflammatory gene expression during tissue injury may contribute to the control of damage and tissue repair, its persistent activation may result in tissue fibrosis and failure of regeneration.
| Original language | English (US) |
|---|---|
| Pages (from-to) | e3000418 |
| Journal | PLoS biology |
| Volume | 17 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2019 |
Fingerprint
ASJC Scopus subject areas
- Neuroscience(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)
- Agricultural and Biological Sciences(all)
Cite this
Activation of the intrinsic fibroinflammatory program in adult pancreatic acinar cells triggered by Hippo signaling disruption. / Liu, Jun; Gao, Ming; Nipper, Michael; Deng, Janice; Sharkey, Francis E; Johnson, Randy L.; Crawford, Howard C.; Chen, Yidong; Wang, Pei.
In: PLoS biology, Vol. 17, No. 9, 01.09.2019, p. e3000418.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Activation of the intrinsic fibroinflammatory program in adult pancreatic acinar cells triggered by Hippo signaling disruption
AU - Liu, Jun
AU - Gao, Ming
AU - Nipper, Michael
AU - Deng, Janice
AU - Sharkey, Francis E
AU - Johnson, Randy L.
AU - Crawford, Howard C.
AU - Chen, Yidong
AU - Wang, Pei
PY - 2019/9/1
Y1 - 2019/9/1
N2 - Damaged acinar cells play a passive role in activating pancreatic stellate cells (PSCs) via recruitment of immune cells that subsequently activate PSCs. However, whether acinar cells directly contribute to PSC activation is unknown. Here, we report that the Hippo pathway, a well-known regulator of proliferation, is essential for suppression of expression of inflammation and fibrosis-associated genes in adult pancreatic acinar cells. Hippo inactivation in acinar cells induced yes-associated protein 1 (YAP1)/transcriptional coactivator with PDZ binding motif (TAZ)-dependent, irreversible fibrosis and inflammation, which was initiated by Hippo-mediated acinar-stromal communications and ameliorated by blocking YAP1/TAZ target connective tissue growth factor (CTGF). Hippo disruption promotes acinar cells to secrete fibroinflammatory factors and induce stromal activation, which precedes acinar proliferation and metaplasia. We found that Hippo disruption did not induce cell-autonomous proliferation but primed acinar cells to exogenous pro-proliferative stimuli, implying a well-orchestrated scenario in which Hippo signaling acts as an intrinsic link to coordinate fibroinflammatory response and proliferation for maintenance of the tissue integrity. Our findings suggest that the fibroinflammatory program in pancreatic acinar cells is suppressed under normal physiological conditions. While transient activation of inflammatory gene expression during tissue injury may contribute to the control of damage and tissue repair, its persistent activation may result in tissue fibrosis and failure of regeneration.
AB - Damaged acinar cells play a passive role in activating pancreatic stellate cells (PSCs) via recruitment of immune cells that subsequently activate PSCs. However, whether acinar cells directly contribute to PSC activation is unknown. Here, we report that the Hippo pathway, a well-known regulator of proliferation, is essential for suppression of expression of inflammation and fibrosis-associated genes in adult pancreatic acinar cells. Hippo inactivation in acinar cells induced yes-associated protein 1 (YAP1)/transcriptional coactivator with PDZ binding motif (TAZ)-dependent, irreversible fibrosis and inflammation, which was initiated by Hippo-mediated acinar-stromal communications and ameliorated by blocking YAP1/TAZ target connective tissue growth factor (CTGF). Hippo disruption promotes acinar cells to secrete fibroinflammatory factors and induce stromal activation, which precedes acinar proliferation and metaplasia. We found that Hippo disruption did not induce cell-autonomous proliferation but primed acinar cells to exogenous pro-proliferative stimuli, implying a well-orchestrated scenario in which Hippo signaling acts as an intrinsic link to coordinate fibroinflammatory response and proliferation for maintenance of the tissue integrity. Our findings suggest that the fibroinflammatory program in pancreatic acinar cells is suppressed under normal physiological conditions. While transient activation of inflammatory gene expression during tissue injury may contribute to the control of damage and tissue repair, its persistent activation may result in tissue fibrosis and failure of regeneration.
UR - http://www.scopus.com/inward/record.url?scp=85072145536&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072145536&partnerID=8YFLogxK
U2 - 10.1371/journal.pbio.3000418
DO - 10.1371/journal.pbio.3000418
M3 - Article
C2 - 31513574
AN - SCOPUS:85072145536
VL - 17
SP - e3000418
JO - PLoS Biology
JF - PLoS Biology
SN - 1544-9173
IS - 9
ER -