Transplanting rejuvenated blood stem cells extends lifespan of aged immunocompromised mice

One goal of regenerative medicine is to rejuvenate tissues and extend lifespan by restoring the function of endogenous aged stem cells. However, evidence that somatic stem cells can be targeted in vivo to extend lifespan is still lacking. Here, we demonstrate that after a short systemic treatment with a specific inhibitor of the small RhoGTPase Cdc42 (CASIN), transplanting aged hematopoietic stem cells (HSCs) from treated mice is sufficient to extend the healthspan and lifespan of aged immunocompromised mice without additional treatment. In detail, we show that systemic CASIN treatment improves strength and endurance of aged mice by increasing the myogenic regenerative potential of aged skeletal muscle stem cells. Further, we show that CASIN modifies niche localization and H4K16ac polarity of HSCs in vivo. Single-cell profiling reveals changes in HSC transcriptome, which underlie enhanced lymphoid and regenerative capacity in serial transplantation assays. Overall, we provide proof-of-concept evidence that a short systemic treatment to decrease Cdc42 activity improves the regenerative capacity of different endogenous aged stem cells in vivo, and that rejuvenated HSCs exert a broad systemic effect sufficient to extend murine health- and lifespan

Application of Artificial Neural Networks in the Prediction of Critical Buckling Loads of Helical Compression Springs

WOS: 000281888500008This paper proposes the use of artificial neural networks (ANN) to perfectly predict the critical buckling loads of cylindrical isotropic helical spring with fixed ends and with circular sections, and with large pitch angles. The buckling equations of cylindrical isotropic helical springs loaded axially consist of a set of twelve linear differential equations. As finding a solution in an analytical manner is too difficult, numerical solution in an exact manner based on the transfer-matrix method to collect consistent dimensionless numerical data for the training process is used. In this way almost perfect weight values are obtained to predict the non-dimensional buckling loads. A good agreement is observed with the data available in the literature. (C)2010 Journal of Mechanical Engineering. All rights reserved.Technical Research Council of Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [106M307]The material covered in this paper is based upon work which was supported by the research grant 106M307 from Technical Research Council of Turkey (TUBITAK)

Aging alters the epigenetic asymmetry of HSC division.

Hematopoietic stem cells (HSCs) balance self-renewal and differentiation to maintain homeostasis. With aging, the frequency of polar HSCs decreases. Cell polarity in HSCs is controlled by the activity of the small RhoGTPase cell division control protein 42 (Cdc42). Here we demonstrate-using a comprehensive set of paired daughter cell analyses that include single-cell 3D confocal imaging, single-cell transplants, single-cell RNA-seq, and single-cell transposase-accessible chromatin sequencing (ATAC-seq)-that the outcome of HSC divisions is strongly linked to the polarity status before mitosis, which is in turn determined by the level of the activity Cdc42 in stem cells. Aged apolar HSCs undergo preferentially self-renewing symmetric divisions, resulting in daughter stem cells with reduced regenerative capacity and lymphoid potential, while young polar HSCs undergo preferentially asymmetric divisions. Mathematical modeling in combination with experimental data implies a mechanistic role of the asymmetric sorting of Cdc42 in determining the potential of daughter cells via epigenetic mechanisms. Therefore, molecules that control HSC polarity might serve as modulators of the mode of stem cell division regulating the potential of daughter cells