Wnts are dispensable for differentiation and self-renewal of adult murine hematopoietic stem cells

Kabiri, Zahra; Numata, Akihiko; Kawasaki, Akira; Edison,; Tenen, Daniel G.; Virshup, David M.

doi:10.1182/blood-2014-09-598540

Cited by 58 publications

(55 citation statements)

References 61 publications

(76 reference statements)

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“…1G). Taken together with conclusions drawn from other in vivo studies using Porcn inhibitors (11,16,17), our observations reveal potential doselimiting on-target activities of Porcn inhibitors in adult mammals, but also reveal possible proregenerative cellular activity in heart tissue with decreased Wnt protein production (Fig. 1H).…”

Section: Resultsmentioning

confidence: 48%

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

Moon

Zhou

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The secreted Wnt signaling molecules are essential to the coordination of cell-fate decision making in multicellular organisms. In adult animals, the secreted Wnt proteins are critical for tissue regeneration and frequently contribute to cancer. Small molecules that disable the Wnt acyltransferase Porcupine (Porcn) are candidate anticancer agents in clinical testing. Here we have systematically assessed the effects of the Porcn inhibitor (WNT-974) on the regeneration of several tissue types to identify potentially unwanted chemical effects that could limit the therapeutic utility of such agents. An unanticipated observation from these studies is proregenerative responses in heart muscle induced by systemic chemical suppression of Wnt signaling. Using in vitro cultures of several cell types found in the heart, we delineate the Wnt signaling apparatus supporting an antiregenerative transcriptional program that includes a subunit of the nonfibrillar collagen VI. Similar to observations seen in animals exposed to WNT-974, deletion of the collagen VI subunit, COL6A1, has been shown to decrease aberrant remodeling and fibrosis in infarcted heart tissue. We demonstrate that WNT-974 can improve the recovery of heart function after left anterior descending coronary artery ligation by mitigating adverse remodeling of infarcted tissue. Injured heart tissue exposed to WNT-974 exhibits decreased scarring and reduced Col6 production. Our findings support the development of Porcn inhibitors as antifibrotic agents that could be exploited to promote heart repair following injury.

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Section: Resultsmentioning

confidence: 48%

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

Moon

Zhou

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…(+,-)/Rosa-LSL-tdTomato(+,-) mice respectively. PORCN inhibitor C59 was synthesized by the Duke University Small Molecule Synthesis facility and administered as described (28). Trametinib was purchased from Chemitek (catalog CT-GSK212) and dissolved in DMSO (10 mg/ml).…”

Section: Author Contributionsmentioning

confidence: 99%

Wnt signaling suppresses MAPK-driven proliferation of intestinal stem cells

Kabiri¹,

Greicius²,

Zaribafzadeh³

et al. 2018

Journal of Clinical Investigation

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“…(48) Moreover, work in Drosophila has demonstrated that non-secreted Wnts might still have a function, shedding a somewhat different light on the absolute requirement of Wnt secretion (49). Whatever the reason, the levels of Axin2 and other Wnt target genes were not affected by Porcn deletion in hematopoietic cells (46), hence no loss-of function model for Wnt signaling was generated. This demonstrates the high complexity and difficulty to generate bona fide null mutants for canonical Wnts in the hematopoietic system.…”

Section: Loss Of Function (Lof) Studies For Wnt Signaling In Hematopomentioning

confidence: 98%

Caught in a Wnt storm: Complexities of Wnt signaling in hematopoiesis

Staal

Chhatta

Mikkers

2016

Experimental Hematology

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Wnts are dispensable for differentiation and self-renewal of adult murine hematopoietic stem cells

Cited by 58 publications

References 61 publications

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

Blockade to pathological remodeling of infarcted heart tissue using a porcupine antagonist

Wnt signaling suppresses MAPK-driven proliferation of intestinal stem cells

Caught in a Wnt storm: Complexities of Wnt signaling in hematopoiesis

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