Ablating Lgr5-expressing prostatic stromal cells activates the ERK-mediated mechanosensory signaling and disrupts prostate tissue homeostasis

Wei, Xing; Zhang, Li; Zhang, Yiqun; Cooper, Cody; Brewer, Chris; Tsai, Chia-Feng; Wang, Yi-Ting; Glaz, Micah; Wessells, Hunter B.; Que, Jianwen; Titus, Mark A.; Cirulli, Vincenzino; Glaser, Adam; Liu, Tao; Reder, Nicholas P.; Creighton, Chad J.; Xin, Li

doi:10.1016/j.celrep.2022.111313

Ablating Lgr5-expressing prostatic stromal cells activates the ERK-mediated mechanosensory signaling and disrupts prostate tissue homeostasis

Journal Article · Tue Sep 06 00:00:00 EDT 2022 · Cell Reports

DOI:https://doi.org/10.1016/j.celrep.2022.111313· OSTI ID:1889463

Wei, Xing ^[1]; Zhang, Li ^[1]; Zhang, Yiqun ^[2]; Cooper, Cody ^[3]; Brewer, Chris ^[3]; Tsai, Chia-Feng ^[4]; Wang, Yi-Ting ^[4]; Glaz, Micah ^[1]; Wessells, Hunter B. ^[1]; Que, Jianwen ^[5]; Titus, Mark A. ^[6]; Cirulli, Vincenzino ^[1]; Glaser, Adam ^[1]; ^[4]; Reder, Nicholas P. ^[3]; Creighton, Chad J. ^[2]; ^[7]

Univ. of Washington, Seattle, WA (United States)
Baylor College of Medicine, Houston, TX (United States)
Alpenglow Biosciences, Inc., Seattle, WA (United States)
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Columbia Univ., New York, NY (United States)
Univ. of Texas, Houston, TX (United States)
Univ. of Washington, Seattle, WA (United States); Univ. of Texas, Houston, TX (United States)

The heterogeneity of the prostate stromal cells is widely appreciated but the functional implication remains incompletely understood. Using genetic lineage tracing and light-sheet imaging, we show that some fibroblast cells near the junction of the mouse proximal prostatic ducts and prostatic urethra highly express Lgr5. Genetic ablation of these anatomically restricted stromal cells, but not nonselective ablation of prostatic stromal cells, rapidly induces prostate epithelial turnover and dedifferentiation that are reversed following spontaneous restoration of the Lgr5⁺ stromal cells. RNA-Seq analysis implies that ablating the Lgr5⁺ stromal cells activates a mechanosensory response. We show that ablating the Lgr5⁺ stromal cells impairs the control of prostatic ductal outlet, increases prostate tissue stiffness, and activates the mitogen-activated protein kinase (MAPK). Suppressing MAPK overrides the increased epithelial proliferation. This study demonstrates that the Lgr5⁺ stromal cells regulate tissue homeostasis in a long-distance manner by maintaining anatomic integrity and implies that the cells near the transitional regions between organs likely control organ homeostasis by sustaining a balanced mechanoforce.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 1889463

Report Number(s):: PNNL-SA-174213

Journal Information:: Cell Reports, Journal Name: Cell Reports Journal Issue: 10 Vol. 40; ISSN 2211-1247

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
Lgr5
MAPK
mechanoforce
prostate
stromal cells

Ablating Lgr5-expressing prostatic stromal cells activates the ERK-mediated mechanosensory signaling and disrupts prostate tissue homeostasis

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