The engraftment of haematopoietic stem and progenitor cells (HSPCs), particularly in cord-blood transplants, remains challenging. Here we report the role of the corticotropin-releasing hormone (CRH) in enhancing the homing and engraftment of human-cord-blood HSPCs in bone marrow through mechanical remodelling. By using microfluidics, intravital two-photon imaging and long-term-engraftment assays, we show that treatment with CRH substantially enhances HSPC adhesion, motility and mechanical remodelling, ultimately leading to improved bone-marrow homing and engraftment in immunodeficient mice. CRH induces Ras homologue gene family member A (RhoA)-dependent nuclear translocation of the yes-associated protein (YAP), which upregulates the expression of genes encoding extracellular-matrix proteins (notably, thrombospondin-2 (THBS2)). This process guides the mechanical remodelling of HSPCs via modulation of the actin cytoskeleton and the extracellular matrix, with THBS2 interacting with the integrin αvβ3 and coordinating the nuclear translocation of YAP upon CRH/CRH-receptor-1 (CRH/CRHR1) signalling. Overall, the CRH/CRHR1/RhoA/YAP/THBS2/αvβ3 axis has a central role in modulating HSPC behaviour via a mechanical feedback loop involving THBS2, αvβ3, the actin cytoskeleton and YAP signalling. Our findings may suggest avenues for optimizing the transplantation of HSPCs.
Ultrasound generates both compressive and shear mechanical forces in soft tissues. However, the specific mechanisms by which these forces activate cellular processes remain unclear. Here we show that low-intensity focused ultrasound can activate the mechanosensitive RET signalling pathway. Specifically, in mouse colon tissues ex vivo and in vivo, focused ultrasound induced RET phosphorylation in colonic crypts cells, which correlated with markers of proliferation and stemness when using hours-long insonication. The activation of the RET pathway is non-thermal, is linearly related to acoustic pressure and is independent of radiation-force-induced shear strain in tissue. Our findings suggest that ultrasound could be used to regulate cell proliferation, particularly in the context of regenerative medicine, and highlight the importance of adhering to current ultrasound-safety regulations for medical imaging.
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