Clonal analysis of Notch1-expressing cells reveals the existence of unipotent stem cells that retain long-term plasticity in the embryonic mammary gland.

Recent lineage tracing studies have revealed that mammary gland homeostasis relies on unipotent stem cells. However, whether and when lineage restriction occurs during embryonic mammary development, and which signals orchestrate cell fate specification, remain unknown. Using a combination of in vivo clonal analysis with whole mount immunofluorescence and mathematical modelling of clonal dynamics, we found that embryonic multipotent mammary cells become lineage-restricted surprisingly early in development, with evidence for unipotency as early as E12.5 and no statistically discernable bipotency after E15.5. To gain insights into the mechanisms governing the switch from multipotency to unipotency, we used gain-of-function Notch1 mice and demonstrated that Notch activation cell autonomously dictates luminal cell fate specification to both embryonic and basally committed mammary cells. These functional studies have important implications for understanding the signals underlying cell plasticity and serve to clarify how reactivation of embryonic programs in adult cells can lead to cancer.Wellcome Trus

Controlled whole body vibration to decrease fall risk and improve health-related quality of life of nursing home residents

Objective: To investigate the effects of whole body vibration in the elderly. Design: Randomized controlled trial. Setting: Nursing home. Participants: Forty-two elderly volunteers. Interventions: Six-week vibration intervention plus physical therapy (PT) (n=22) or PT alone (n=20). Main Outcome Measures: We assessed gait and body balance using the Tinetti test (maximum scores of 12 for gait, 16 for body balance, 28 for global score), motor capacity using the Timed Up & Go (TUG) test, and health-related quality of life (HRQOL) using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Results: After 6 weeks, the vibration intervention group improved by a mean +/- standard deviation of 2.4 +/- 2.3 points on the gait score compared with no score change in the control group (P<.001). The intervention group improved by 3.5 +/- 2.1 points on the body balance score compared with a decrease of 03 +/- 1.2 points in the control group (P<.001). TUG test time decreased by 11.0 +/- 8.6 seconds in the treated group compared with an increase of 2.6 +/- 8.8 seconds in the control group (P<.001). The intervention group had significantly greater improvements from baseline on 8 of 9 items on the SF-36 compared with the control group. Conclusions: Controlled whole body vibration can improve elements of fall risk and HRQOL in elderly patients

Controlled whole body vibration to decrease fall risk and improve health related quality of life in elderly patients

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Insc:LGN tetramers promote asymmetric divisions of mammary stem cells

Asymmetric cell divisions balance stem cell proliferation and differentiation to sustain tissue morphogenesis and homeostasis. During asymmetric divisions, fate determinants and niche contacts segregate unequally between daughters, but little is known on how this is achieved mechanistically. In Drosophila neuroblasts and murine mammary stem cells, the association of the spindle orientation protein LGN with the stem cell adaptor Inscuteable has been connected to asymmetry. Here we report the crystal structure of Drosophila LGN in complex with the asymmetric domain of Inscuteable, which reveals a tetrameric arrangement of intertwined molecules. We show that Insc:LGN tetramers constitute stable cores of Par3-Insc-LGN-GαiGDP complexes, which cannot be dissociated by NuMA. In mammary stem cells, the asymmetric domain of Insc bound to LGN:GαiGDP suffices to drive asymmetric fate, and reverts aberrant symmetric divisions induced by p53 loss. We suggest a novel role for the Insc-bound pool of LGN acting independently of microtubule motors to promote asymmetric fate specification

Early lineage segregation of multipotent embryonic mammary gland progenitors.

The mammary gland is composed of basal cells and luminal cells. It is generally believed that the mammary gland arises from embryonic multipotent progenitors, but it remains unclear when lineage restriction occurs and what mechanisms are responsible for the switch from multipotency to unipotency during its morphogenesis. Here, we perform multicolour lineage tracing and assess the fate of single progenitors, and demonstrate the existence of a developmental switch from multipotency to unipotency during embryonic mammary gland development. Molecular profiling and single cell RNA-seq revealed that embryonic multipotent progenitors express a unique hybrid basal and luminal signature and the factors associated with the different lineages. Sustained p63 expression in embryonic multipotent progenitors promotes unipotent basal cell fate and was sufficient to reprogram adult luminal cells into basal cells by promoting an intermediate hybrid multipotent-like state. Altogether, this study identifies the timing and the mechanisms mediating early lineage segregation of multipotent progenitors during mammary gland development.SCOPUS: ar.jSCOPUS: er.jinfo:eu-repo/semantics/publishe