Notch-mediated Sox9 + cell activation contributes to kidney repair after partial nephrectomy

Ma, Qiwang; Wang, Yujia; Zhang, Ting; Zuo, Wei

doi:10.1016/j.lfs.2017.11.041

Cited by 19 publications

(17 citation statements)

References 25 publications

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“…The effect of abrogating Notch1 function appears to be specific for keratinocytes, since deletion of Notch1 signaling in macrophages does not exert a similar effect on wound healing (23). The cell-type-specific diversity in the Notchsignaling output is not restricted to the skin, since in the kidney, Notch signaling has opposite effects in podocytes (49) compared with tubular precursor cells (50). The fact that Notch signaling negatively regulates the expression of SDF-1 (29) and CXCR4 (30), which are important factors for EPC recruitment, may provide a mechanism for how Notch regulates angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Triggering of a Dll4–Notch1 loop impairs wound healing in diabetes

Zheng

Narayanan

Sunkari

et al. 2019

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

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Diabetic foot ulcerations (DFUs) represent a major medical, social, and economic problem. Therapeutic options are restricted due to a poor understanding of the pathogenic mechanisms. The Notch pathway plays a pivotal role in cell differentiation, proliferation, and angiogenesis, processes that are profoundly disturbed in diabetic wounds. Notch signaling is activated upon interactions between membrane-bound Notch receptors (Notch 1–4) and ligands (Jagged 1–2 and Delta-like 1, 3, 4), resulting in cell-context-dependent outputs. Here, we report that Notch1 signaling is activated by hyperglycemia in diabetic skin and specifically impairs wound healing in diabetes. Local inhibition of Notch1 signaling in experimental wounds markedly improves healing exclusively in diabetic, but not in nondiabetic, animals. Mechanistically, high glucose levels activate a specific positive Delta-like 4 (Dll4)–Notch1 feedback loop. Using loss-of-function genetic approaches, we demonstrate that Notch1 inactivation in keratinocytes is sufficient to cancel the repressive effects of the Dll4–Notch1 loop on wound healing in diabetes, thus making Notch1 signaling an attractive locally therapeutic target for the treatment of DFUs.

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Section: Discussionmentioning

confidence: 99%

Triggering of a Dll4–Notch1 loop impairs wound healing in diabetes

Zheng

Narayanan

Sunkari

et al. 2019

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

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“…Indeed, these Sox9-positive cells showed high level of Notch signaling and overexpression of NICD1 in the Sox9-positive population showed improved renal histology [81]. More recently, in a model of left kidney partial nephrectomy, the Notch inhibitor DAPT was found to abolish the increase of Sox9-positive cells, showing Notch to be a key player in regulating epithelial repair in kidney regeneration after injury (Figure 2) [84].…”

Section: Notch Signaling In Adult Kidney Maintenance Repair and mentioning

confidence: 99%

Notch Signaling in Kidney Development, Maintenance, and Disease

et al. 2019

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Kidney development involves formation of nephrons intricately aligned with the vasculature and connected to a branched network of collecting ducts. Notch signaling plays multiple roles during kidney development involving the formation of nephrons composed of diverse epithelial cell types arranged into tubular segments, all the while maintaining a nephron progenitor niche. Here, we review the roles of Notch signaling identified from rodent kidney development and injury studies, while discussing human kidney diseases associated with aberrant Notch signaling. We also review Notch signaling requirement in maintenance of mature kidney epithelial cell states and speculate that Notch activity regulation mediates certain renal physiologic adaptations.

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“…Lineage tracing is recently being used as a powerful tool in tissue regeneration and stem cell research by labeling a specific type of cells, which offers an opportunity to visualize the cell behavior in the context of the intact organism instead of the in vitro environment (18)(19)(20). The research based on the lineage tracing of Sox9 1 cell mouse models provides novel insight into the Sox9 1 cells in renal development, the cell fate during renal injury, and the potential mechanisms of renal regeneration (3,4,21). However, the conventional research method of lineage tracing relying on sacrificing the animals to get the information on the tissue sections is only a "snapshot" (19,22), which is unable to dynamically monitor the Sox9 1 cell behavior in action.…”

mentioning

confidence: 99%

In vivo two-photon microscopy reveals the contribution of Sox9+ cell to kidney regeneration in a mouse model with extracellular vesicle treatment

Zhang

Shang

Sun

et al. 2020

Journal of Biological Chemistry

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Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) have been shown to stimulate regeneration in the treatment of kidney injury. Renal regeneration is also thought to be stimulated by the activation of Sox9+ cells. However, whether and how the activation mechanisms underlying EV treatment and Sox9+ cell-dependent regeneration intersect is unclear. We reasoned that a high-resolution imaging platform in living animals could help to untangle this system. To test this idea, we first applied EVs derived from human placenta-derived MSCs (hP-MSCs) to a Sox9-CreERT2; R26mTmG transgenic mouse model of acute kidney injury (AKI). Then, we developed an abdominal imaging window (AIW) in the mouse and tracked the Sox9+ cells in the inducible Sox9 Cre transgenic mice via in vivo lineage tracing with two-photon intravital microscopy. Our results demonstrated that EVs can travel to the injured kidneys post intravenous injection as visualized by Gaussia luciferase imaging and markedly increased the activation of Sox9+ cells. Moreover, the two-photon living imaging of lineage-labeled Sox9+ cells showed that the EVs promoted the expansion of Sox9+ cells in kidneys post AKI. Histological staining results confirmed that the descendants of Sox9+ cells contributed to nephric tubule regeneration which significantly ameliorated the renal function after AKI. In summary, intravital lineage tracing with two-photon microscopy through an embedded AIW provides a practical strategy to investigate the beneficial functions and to clarify the mechanisms of regenerative therapies in AKI.

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Notch-mediated Sox9 + cell activation contributes to kidney repair after partial nephrectomy

Cited by 19 publications

References 25 publications

Triggering of a Dll4–Notch1 loop impairs wound healing in diabetes

Triggering of a Dll4–Notch1 loop impairs wound healing in diabetes

Notch Signaling in Kidney Development, Maintenance, and Disease

In vivo two-photon microscopy reveals the contribution of Sox9+ cell to kidney regeneration in a mouse model with extracellular vesicle treatment

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