TY - JOUR
T1 - Stiffness Restricts the Stemness of the Intestinal Stem Cells and Skews Their Differentiation Toward Goblet Cells
AU - He, Shijie
AU - Lei, Peng
AU - Kang, Wenying
AU - Cheung, Priscilla
AU - Xu, Tao
AU - Mana, Miyeko
AU - Park, Chan Young
AU - Wang, Hongyan
AU - Imada, Shinya
AU - Russell, Jacquelyn O.
AU - Wang, Jianxun
AU - Wang, Ruizhi
AU - Zhou, Ziheng
AU - Chetal, Kashish
AU - Stas, Eric
AU - Mohad, Vidisha
AU - Bruun-Rasmussen, Peter
AU - Sadreyev, Ruslan I.
AU - Hodin, Richard A.
AU - Zhang, Yanhang
AU - Breault, David T.
AU - Camargo, Fernando D.
AU - Yilmaz, Ömer H.
AU - Fredberg, Jeffrey J.
AU - Saeidi, Nima
N1 - Publisher Copyright:
© 2023 AGA Institute
PY - 2023/6
Y1 - 2023/6
N2 - Background & Aims: Fibrosis and tissue stiffening are hallmarks of inflammatory bowel disease (IBD). We have hypothesized that the increased stiffness directly contributes to the dysregulation of the epithelial cell homeostasis in IBD. Here, we aim to determine the impact of tissue stiffening on the fate and function of the intestinal stem cells (ISCs). Methods: We developed a long-term culture system consisting of 2.5-dimensional intestinal organoids grown on a hydrogel matrix with tunable stiffness. Single-cell RNA sequencing provided stiffness-regulated transcriptional signatures of the ISCs and their differentiated progeny. YAP-knockout and YAP-overexpression mice were used to manipulate YAP expression. In addition, we analyzed colon samples from murine colitis models and human IBD samples to assess the impact of stiffness on ISCs in vivo. Results: We demonstrated that increasing the stiffness potently reduced the population of LGR5+ ISCs and KI-67+–proliferating cells. Conversely, cells expressing the stem cell marker, olfactomedin-4, became dominant in the crypt-like compartments and pervaded the villus-like regions. Concomitantly, stiffening prompted the ISCs to preferentially differentiate toward goblet cells. Mechanistically, stiffening increased the expression of cytosolic YAP, driving the extension of olfactomedin-4+ cells into the villus-like regions, while it induced the nuclear translocation of YAP, leading to preferential differentiation of ISCs toward goblet cells. Furthermore, analysis of colon samples from murine colitis models and patients with IBD demonstrated cellular and molecular remodeling reminiscent of those observed in vitro. Conclusions: Collectively, our findings highlight that matrix stiffness potently regulates the stemness of ISCs and their differentiation trajectory, supporting the hypothesis that fibrosis-induced gut stiffening plays a direct role in epithelial remodeling in IBD.
AB - Background & Aims: Fibrosis and tissue stiffening are hallmarks of inflammatory bowel disease (IBD). We have hypothesized that the increased stiffness directly contributes to the dysregulation of the epithelial cell homeostasis in IBD. Here, we aim to determine the impact of tissue stiffening on the fate and function of the intestinal stem cells (ISCs). Methods: We developed a long-term culture system consisting of 2.5-dimensional intestinal organoids grown on a hydrogel matrix with tunable stiffness. Single-cell RNA sequencing provided stiffness-regulated transcriptional signatures of the ISCs and their differentiated progeny. YAP-knockout and YAP-overexpression mice were used to manipulate YAP expression. In addition, we analyzed colon samples from murine colitis models and human IBD samples to assess the impact of stiffness on ISCs in vivo. Results: We demonstrated that increasing the stiffness potently reduced the population of LGR5+ ISCs and KI-67+–proliferating cells. Conversely, cells expressing the stem cell marker, olfactomedin-4, became dominant in the crypt-like compartments and pervaded the villus-like regions. Concomitantly, stiffening prompted the ISCs to preferentially differentiate toward goblet cells. Mechanistically, stiffening increased the expression of cytosolic YAP, driving the extension of olfactomedin-4+ cells into the villus-like regions, while it induced the nuclear translocation of YAP, leading to preferential differentiation of ISCs toward goblet cells. Furthermore, analysis of colon samples from murine colitis models and patients with IBD demonstrated cellular and molecular remodeling reminiscent of those observed in vitro. Conclusions: Collectively, our findings highlight that matrix stiffness potently regulates the stemness of ISCs and their differentiation trajectory, supporting the hypothesis that fibrosis-induced gut stiffening plays a direct role in epithelial remodeling in IBD.
KW - Fibrosis
KW - IBD
KW - Intestinal Organoids
KW - Intestinal Stem Cells
KW - Stiffening
UR - http://www.scopus.com/inward/record.url?scp=85153799229&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85153799229&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2023.02.030
DO - 10.1053/j.gastro.2023.02.030
M3 - Article
C2 - 36871599
AN - SCOPUS:85153799229
SN - 0016-5085
VL - 164
SP - 1137-1151.e15
JO - Gastroenterology
JF - Gastroenterology
IS - 7
ER -