A Subpopulation of Adult Skeletal Muscle Stem Cells Retains All Template DNA Strands after Cell Division

SummarySatellite cells are adult skeletal muscle stem cells that are quiescent and constitute a poorly defined heterogeneous population. Using transgenic Tg:Pax7-nGFP mice, we show that Pax7-nGFPHi cells are less primed for commitment and have a lower metabolic status and delayed first mitosis compared to Pax7-nGFPLo cells. Pax7-nGFPHi can give rise to Pax7-nGFPLo cells after serial transplantations. Proliferating Pax7-nGFPHi cells exhibit lower metabolic activity, and the majority performs asymmetric DNA segregation during cell division, wherein daughter cells retaining template DNA strands express stem cell markers. Using chromosome orientation-fluorescence in situ hybridization, we demonstrate that all chromatids segregate asymmetrically, whereas Pax7-nGFPLo cells perform random DNA segregation. Therefore, quiescent Pax7-nGFPHi cells represent a reversible dormant stem cell state, and during muscle regeneration, Pax7-nGFPHi cells generate distinct daughter cell fates by asymmetrically segregating template DNA strands to the stem cell. These findings provide major insights into the biology of stem cells that segregate DNA asymmetrically

A Subpopulation of Adult Skeletal Muscle Stem Cells Retains All Template DNA Strands after Cell Division

SummarySatellite cells are adult skeletal muscle stem cells that are quiescent and constitute a poorly defined heterogeneous population. Using transgenic Tg:Pax7-nGFP mice, we show that Pax7-nGFPHi cells are less primed for commitment and have a lower metabolic status and delayed first mitosis compared to Pax7-nGFPLo cells. Pax7-nGFPHi can give rise to Pax7-nGFPLo cells after serial transplantations. Proliferating Pax7-nGFPHi cells exhibit lower metabolic activity, and the majority performs asymmetric DNA segregation during cell division, wherein daughter cells retaining template DNA strands express stem cell markers. Using chromosome orientation-fluorescence in situ hybridization, we demonstrate that all chromatids segregate asymmetrically, whereas Pax7-nGFPLo cells perform random DNA segregation. Therefore, quiescent Pax7-nGFPHi cells represent a reversible dormant stem cell state, and during muscle regeneration, Pax7-nGFPHi cells generate distinct daughter cell fates by asymmetrically segregating template DNA strands to the stem cell. These findings provide major insights into the biology of stem cells that segregate DNA asymmetrically

Towards a canonical classical natural deduction system

This paper studies a new classical natural deduction system, presented as a typed calculus named \lml. It is designed to be isomorphic to Curien-Herbelin's calculus, both at the level of proofs and reduction, and the isomorphism is based on the correct correspondence between cut (resp. left-introduction) in sequent calculus, and substitution (resp. elimination) in natural deduction. It is a combination of Parigot's $\lambda\mu$-calculus with the idea of ``coercion calculus'' due to Cervesato-Pfenning, accommodating let-expressions in a surprising way: they expand Parigot's syntactic class of named terms. This calculus aims to be the simultaneous answer to three problems. The first problem is the lack of a canonical natural deduction system for classical logic. \lml is not yet another classical calculus, but rather a canonical reflection in natural deduction of the impeccable treatment of classical logic by sequent calculus. The second problem is the lack of a formalization of the usual semantics of Curien-Herbelin's calculus, that explains co-terms and cuts as, respectively, contexts and hole-filling instructions. The mentioned isomorphism is the required formalization, based on the precise notions of context and hole-expression offered by \lml. The third problem is the lack of a robust process of ``read-back'' into natural deduction syntax of calculi in the sequent calculus format, that affects mainly the recent proof-theoretic efforts of derivation of $\lambda$-calculi for call-by-value. An isomorphic counterpart to the $Q$-subsystem of Curien-Herbelin's-calculus is derived, obtaining a new $\lambda$-calculus for call-by-value, combining control and let-expressions.Fundação para a Ciência e a Tecnologia (FCT

Precautionary Demand for Money in a Monetary Business Cycle Model

We investigate the quantitative implications of precautionary demand for money for business cycle dynamics of velocity of money and other nominal aggregates. There is a standing challenge in monetary macroeconomics to account for business cycle dynamics of nominal variables, as previous business cycle models that have tried to incorporate demand for money have failed to generate realistic predictions in this regard. Our stance is that part of this failure results from the fact that demand for money in those previous models is deterministic, since agents in them face only aggregate risk, whereas we believe idiosyncratic risk to be important as well. We conduct the exercise inside a monetary search model, as our additional goal is to put to the test a recent generation of such frictional models to examine whether their quantitative predictions are realistic, and whether they generate additional insight into business cycle data that non-search models of money cannot generate. On the first question, our results suggest that precautionary demand for money plays a substantial role i

The aged niche disrupts muscle stem cell quiescence

SUMMARY The niche is a conserved regulator of stem cell quiescence and function. During aging, stem cell function declines. To what extent and by which means age-related changes within the niche contribute to this phenomenon are unknown. We demonstrate that the aged muscle stem cell niche, the muscle fiber, expresses FGF2 under homeostatic conditions, driving a subset of satellite cells to break quiescence and lose self-renewing capacity. We show that relatively dormant aged satellite cells robustly express Sprouty1 (spry1), an inhibitor of FGF signalling. Increasing FGF signalling in aged satellite cells under homeostatic conditions by removing spry1, results in the loss of quiescence, satellite cell depletion and diminished regenerative capacity. Conversely, reducing niche-derived FGF activity through inhibition of FGFR1 signalling or overexpression of spry1 in satellite cells prevents their depletion. These experiments identify an age-dependent change in the stem cell niche that directly influences stem cell quiescence and function

Plasticity of the Muscle Stem Cell Microenvironment

Satellite cells (SCs) are adult muscle stem cells capable of repairing damaged and creating new muscle tissue throughout life. Their functionality is tightly controlled by a microenvironment composed of a wide variety of factors, such as numerous secreted molecules and different cell types, including blood vessels, oxygen, hormones, motor neurons, immune cells, cytokines, fibroblasts, growth factors, myofibers, myofiber metabolism, the extracellular matrix and tissue stiffness. This complex niche controls SC biology-quiescence, activation, proliferation, differentiation or renewal and return to quiescence. In this review, we attempt to give a brief overview of the most important players in the niche and their mutual interaction with SCs. We address the importance of the niche to SC behavior under physiological and pathological conditions, and finally survey the significance of an artificial niche both for basic and translational research purposes