R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon

Harnack, Christine; Berger, Hilmar; Antanaviciute, Agne; Vidal, Ramón; Sauer, Sascha; Simmons, Alison; Meyer, Thomas F.; Sigal, Michael

doi:10.1038/s41467-019-12349-5

Cited by 98 publications

(74 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This is a unique finding when compared to recent single cell studies in the adult human colon, and compared to findings in the mouse. In the adult human colon, a source of WNT and RSPO external to the muscular mucosae has been identified as WNT2B/RSPO3+ fibroblasts (Smillie et al, 2019), whereas in mice the predominant source of RSPO3 are PDGRFA+ cells in the small intestine (Greicius et al, 2018), or MYH11+ myofibroblasts in the colon (Harnack et al, 2019). In addition, the identification of the Foxl1 + telocyte has represented a major advance in elucidating the cells and sources of many niche factors in the murine intestinal stem cell niche (Aoki et al, 2016; Shoshkes-Carmel et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo development of the human intestinal niche at single cell resolution

Czerwinski

Holloway

Tsai

et al. 2020

Preprint

View full text Add to dashboard Cite

SUMMARYThe human intestinal stem cell (ISC) niche supports ISC self-renewal and epithelial function, yet little is known about the development of the human ISC niche. We used single-cell mRNA sequencing (scRNA-seq) to interrogate the human intestine across 7-21 weeks of gestation. Using these data coupled with marker validation in situ, molecular identities and spatial locations were assigned to several cell populations that comprise the epithelial niche, and the cellular origins of many niche factors were determined. The major source of WNT and RSPONDIN ligands were ACTA2+ cells of the muscularis mucosa. EGF was predominantly expressed in the villus epithelium and the EGF-family member NEUREGULIN1 (NRG1) was expressed by subepithelial mesenchymal cells. Functional data from enteroid cultures showed that NRG1 improved cellular diversity, enhanced the stem cell gene signature, and increased enteroid forming efficiency, whereas EGF supported a secretory gene expression profile and stimulated rapid proliferation. This work highlights unappreciated complexities of intestinal EGF/ERBB signaling and identifies NRG1 as a stem cell niche factor.

show abstract

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo development of the human intestinal niche at single cell resolution

Czerwinski

Holloway

Tsai

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Mesenchymal stem cells (MSCs) have a significant therapeutic potential for tissue damage by improving the growth of intestinal crypts in vitro by activating the Wnt/β-catenin signalling pathway [47]. Similarly, stromal myofibroblasts through secreted Rspo3 proteins can stabilise the effects of Wnt ligands and further reprogram differentiated cells to support crypt regeneration upon damage [48]. A recent study showed that fibroblasts could secrete extracellular vesicles with Wnt and EGF activity, thereby rescuing Wnt-or EGF-deficient organoid growth [49].…”

Section: Stromal Cells Inflammatory Cells and Cytokine Mediators Invmentioning

confidence: 99%

Plasticity of Paneth cells and their ability to regulate intestinal stem cells

Mei

2020

Stem Cell Res Ther

View full text Add to dashboard Cite

Paneth cells (PCs) are located at the bottom of small intestinal crypts and play an important role in maintaining the stability of the intestinal tract. Previous studies reported on how PCs shape the intestinal microbiota or the response to the immune system. Recent studies have determined that PCs play an important role in the regulation of the homeostasis of intestinal epithelial cells. PCs can regulate the function and homeostasis of intestinal stem cells through several mechanisms. On the one hand, under pathological conditions, PCs can be dedifferentiated into stem cells to promote the repair of intestinal tissues. On the other hand, PCs can regulate stem cell proliferation by secreting a variety of hormones (such as wnt3a) or metabolic intermediates. In addition, we summarise key signalling pathways that affect PC differentiation and mutual effect with intestinal stem cells. In this review, we introduce the diverse functions of PCs in the intestine.

show abstract

“…Interestingly, all markers that have a favorable prognostic significance are SC markers which predominantly exhibited a basal expression pattern in early GCs, and the proportion of marker-positive cancer cells increased in submucosal invasion. Therefore, it seems less likely that SC marker expression has any functional implication in the [29,30,37]. We hypothesized that the niche factors released from MM upregulate ISC markers, such as EPHB2 or LGR5, in the basal areas of GCs.…”

Section: Discussionmentioning

confidence: 99%

“…human stomach (Supplementary Figure S8b), whereas in the mouse stomach and colon only RSPO3 was shown to be expressed in the MM and to play essential roles for stem cell reprogramming [29,37].…”

Section: Discussionmentioning

confidence: 99%

Expression of Intestinal Stem Cell and Cancer Stem Cell Markers in Submucosal Invasion and Its Prognostic Significance in Gastric Cancers

Kim¹,

Song²,

Jeong³

et al. 2020

Preprint

View full text Add to dashboard Cite

Submucosal invasion is a critical step in gastric cancer (GC) progression, which greatly enhances metastasis risk. Cancer stem cells are responsible for invasion, metastasis, and tumor growth. To identify stem cell-related markers associated with submucosal invasion in GCs, we investigated the expression of candidate cancer stem cell (CSC) markers (CD133, CD44, and ALDH1A) and intestinal stem cell (ISC) markers (EPHB2, OLFM4, and LGR5) in early GCs with submucosal invasion. Remarkably, expression of all ISC markers and CD133 was frequently confined to the basal area of the lamina propria (basal pattern) in mucosal cancer. The proportion of stem cell marker-positive cells substantially increased during submucosal invasion. Given that ISC markers are restricted to the crypt base of the normal intestinal mucosa, these findings suggest that many early GCs may retain hierarchical characteristics. CD44 expression showed a focal pattern, ALDH1A was predominantly expressed diffusely, and there was no expansion of CD44 or ALDH1A expression in the submucosal cancer cells. RSPO2 from muscularis mucosa seem to be partly responsible for the increased expression of ISC markers in GC cells at the basal areas. We also found that ISC markers were correlated with CDX2 expression in GCs, indicating that ISC markers are involved in the intestinal differentiation in GCs. Interestingly, ISC markers (EPHB2 and OLFM4) and CD133 showed a positive impact on clinical outcomes. In particular, the prognostic value of EPHB2 was significant for intestinal-type GCs in a multivariate analysis. In summary, ISC markers and CD133 showed a basal distribution pattern along with enhanced expression in submucosal invading cells in early GCs. EPHB2 was an independent prognostic marker in intestinal-type GCs.

show abstract

R-spondin 3 promotes stem cell recovery and epithelial regeneration in the colon

Cited by 98 publications

References 39 publications

In vitro and in vivo development of the human intestinal niche at single cell resolution

In vitro and in vivo development of the human intestinal niche at single cell resolution

Plasticity of Paneth cells and their ability to regulate intestinal stem cells

Expression of Intestinal Stem Cell and Cancer Stem Cell Markers in Submucosal Invasion and Its Prognostic Significance in Gastric Cancers

Contact Info

Product

Resources

About