Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell

Ayyaz, Arshad; Kumar, Sandeep; Sangiorgi, Bruno; Ghoshal, Bibaswan; Gosio, Jessica; Ouladan, Shaida; Fink, Mardi; Barutcu, Seda; Trcka, Daniel; Shen, Jess; Chan, Kin; Wrana, Jeffrey L.; Gregorieff, Alex

doi:10.1038/s41586-019-1154-y

Cited by 396 publications

(493 citation statements)

References 43 publications

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“…Our data show that YAP/TAZ signaling can be potent driver of survival and proliferation in intestinal cancer cells, independent of WNT activation. This mirrors a recently described role for YAP/TAZ in normal tissue regeneration following colitis (33) and/or irradiation-induced mucosal damage (31). In both cases, YAP-mediated repair is associated with upregulation of fetal markers, though it is unclear whether the regenerating epithelium, like fetal organoids (28), are WNT-independent.…”

Section: Discussionsupporting

confidence: 81%

Lineage reversion drives WNT independence in intestinal cancer

Han

Goswami

et al. 2020

Preprint

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The WNT pathway is a fundamental regulator of intestinal homeostasis and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer (CRC). To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that while WNT suppression blocks tumor growth in most organoid and in vivo CRC models, the accumulation of CRC-associated genetic alterations enables drug resistance and WNTindependent growth. In intestinal epithelial cells harboring mutations in KRAS or BRAF, together with disruption of p53 and SMAD4, transient TGFb exposure drives YAP/ TAZ-dependent transcriptional reprogramming and lineage reversion. Acquisition of embryonic intestinal identity is accompanied by a permanent loss of adult intestinal lineages, and long-term WNT-independent growth. This work delineates genetic and microenvironmental factors that drive WNT inhibitor resistance, identifies a new mechanism for WNT-independent CRC growth and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs.

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Section: Discussionsupporting

confidence: 81%

Lineage reversion drives WNT independence in intestinal cancer

Han

Goswami

et al. 2020

Preprint

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“…Although our data indicate that it is the rapidly-cycling Msi1 + ISCs that survive irradiation exposure and repopulate damaged epithelium, we cannot formally rule out the previously proposed model that quiescent ISCs and/or precursors also contribute to epithelial regeneration (Ayyaz, Kumar et al, 2019, Chaves-Perez, Yilmaz et al, 2019, Yan et al, 2017. It is noteworthy that, while many secretory progenitor cells, marked by Dll1-CreERT (van Es et al, 2012), Prox1-CreERT (Yan et al, 2017), or H2B-label (Buczacki et al, 2013), have regenerative capacity, the contribution of these cells to epithelial regeneration are limited (Bankaitis, Ha et al, 2018).…”

Section: Discussioncontrasting

confidence: 73%

Rapidly cycling stem cells regenerate the intestine independent ofLgr5^highcells

Sheng

Lin

et al. 2019

Preprint

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The +4 cells in intestinal crypts are DNA damage-resistant and contribute to regeneration. However, their exact identity and the mechanism underlying +4 cell-mediated regeneration remain unclear. Using lineage tracing, we show that cells marked by an Msi1 reporter (Msi1 + ) are enriched at the +4 position in intestinal crypts and exhibit DNA damage resistance. Single-cell RNA sequencing reveals that the Msi1 + cells are heterogeneous with the majority being intestinal stem cells (ISCs). The DNA damage-resistant subpopulation of Msi1 + cells is characterized by low-to-negative Lgr5 expression and is more rapidly cycling than Lgr5 high radio-sensitive crypt base columnar stem cells (CBCs); they enable fast repopulation of the intestinal epithelium independent of CBCs that are largely depleted after irradiation. Furthermore, relative to CBCs, Msi1 + cells preferentially produce Paneth cells during homeostasis and upon radiation repair. Together, we demonstrate that the DNA damage-resistant Msi1 + cells are rapidly cycling ISCs that maintain and regenerate the intestinal epithelium.

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“…However, it does not explain the expansion 215 of ISCs, the complete loss of PCs, or the lack of expansion of mature ChgA + cells that we 216 observe in KO epithelium, which thus contradict a primarily GFI1-mediated mechanism. 217 218 Over the years, there have been various different intestinal stem cell and stem-cell like 219 populations described, either using genetic markers such as Lgr5 or Bmi1, or by techniques 220 such as label-retaining capacity and scRNA-seq (Yan et al, 2017;Buczacki et al, 2013;van 221 Es et al, 2012;Ayyaz et al, 2019;Muñoz et al, 2012). To test if there was enrichment for a 222 certain stem cell type, we analyzed expression of defining genes for each population (Fig.…”

mentioning

confidence: 99%

LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

Zwiggelaar

Lindholm

Fosslie

et al. 2020

Preprint

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30Intestinal epithelial homeostasis is maintained by adult intestinal stem cells, which, alongside 31 Paneth cells, appear after birth in the neonatal period. We aimed to identify new regulators of 32 neonatal intestinal epithelial development by testing a small library of epigenetic modifier 33 inhibitors in Paneth cell-skewed organoid cultures. We found that Lysine-specific 34 demethylase 1A (Kdm1a/Lsd1) is absolutely required for Paneth cell differentiation. Lsd1-35 deficient crypts, devoid of Paneth cells, are still able to form organoids without a requirement 36 of exogenous or endogenous Wnt. Mechanistically, we find that LSD1 represses genes that 37 are normally expressed in fetal and neonatal epithelium. This gene profile is similar to what is 38 seen in repairing epithelium, and indeed, we find that Lsd1-deficient epithelium has superior 39 regenerative capacities after irradiation injury. In summary, we found an important regulator 40 of neonatal intestinal development and identified a druggable target to reprogram intestinal 41 epithelium towards a reparative state. 42indicate PC + crypts based on presence of granular cells, asterisks indicate PCcrypts. D, Brightfield images and

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Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell

Cited by 396 publications

References 43 publications

Lineage reversion drives WNT independence in intestinal cancer

Lineage reversion drives WNT independence in intestinal cancer

Rapidly cycling stem cells regenerate the intestine independent ofLgr5^highcells

LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

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Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell

Cited by 396 publications

References 43 publications

Lineage reversion drives WNT independence in intestinal cancer

Lineage reversion drives WNT independence in intestinal cancer

Rapidly cycling stem cells regenerate the intestine independent ofLgr5highcells

LSD1 represses a neonatal/reparative gene program in adult intestinal epithelium

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Rapidly cycling stem cells regenerate the intestine independent ofLgr5^highcells