Villeda S.A.,University of California at San Francisco |
Villeda S.A.,Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research |
Villeda S.A.,Stanford University |
Plambeck K.E.,University of California at San Francisco |
And 24 more authors.
Nature Medicine | Year: 2014
As human lifespan increases, a greater fraction of the population is suffering from age-related cognitive impairments, making it important to elucidate a means to combat the effects of aging. Here we report that exposure of an aged animal to young blood can counteract and reverse pre-existing effects of brain aging at the molecular, structural, functional and cognitive level. Genome-wide microarray analysis of heterochronic parabionts - in which circulatory systems of young and aged animals are connected - identified synaptic plasticity-related transcriptional changes in the hippocampus of aged mice. Dendritic spine density of mature neurons increased and synaptic plasticity improved in the hippocampus of aged heterochronic parabionts. At the cognitive level, systemic administration of young blood plasma into aged mice improved age-related cognitive impairments in both contextual fear conditioning and spatial learning and memory. Structural and cognitive enhancements elicited by exposure to young blood are mediated, in part, by activation of the cyclic AMP response element binding protein (Creb) in the aged hippocampus. Our data indicate that exposure of aged mice to young blood late in life is capable of rejuvenating synaptic plasticity and improving cognitive function. © 2014 Nature America, Inc. All rights reserved.
Robinson J.F.,Center for Reproductive science |
Robinson J.F.,Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research |
Fisher S.J.,Center for Reproductive science |
Fisher S.J.,Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research |
Fisher S.J.,University of California at San Francisco
Cell Research | Year: 2014
Implantation involves complex signaling networks, which direct morphological and molecular transformation of the embryo and the uterus and establish the trajectory of normal pregnancy. The recent work by Zhang et al. published in Cell Research, identifies the transcriptional regulator, Rbpj, as essential for uterine closure and proper embryo alignment during implantation in the mouse, raising the possibility that aberrant Rbpj signaling could contribute to infertility in humans. © 2014 IBCB, SIBS, CAS.
Rountree C.B.,Penn State College of Medicine |
Mishra L.,University of Texas M. D. Anderson Cancer Center |
Willenbring H.,Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research |
Willenbring H.,University of California at San Francisco
Hepatology | Year: 2012
Stem cells have potential for therapy of liver diseases, but may also be involved in the formation of liver cancer. Recently, the American Association for the Study of Liver Diseases Henry M. and Lillian Stratton Basic Research Single Topic Conference "Stem Cells in Liver Diseases and Cancer: Discovery and Promise" brought together a diverse group of investigators to define the status of research on stem cells and cancer stem cells in the liver and identify problems and solutions on the path to clinical translation. This report summarizes the outcomes of the conference and provides an update on recent research advances. Progress in liver stem cell research includes isolation of primary liver progenitor cells (LPCs), directed hepatocyte differentiation of primary LPCs and pluripotent stem cells, findings of transdifferentiation, disease-specific considerations for establishing a therapeutically effective cell mass, and disease modeling in cell culture. Tumor-initiating stem-like cells (TISCs) that emerge during chronic liver injury share the expression of signaling pathways, including those organized around transforming growth factor beta and β-catenin, and surface markers with normal LPCs. Recent investigations of the role of TISCs in hepatocellular carcinoma have provided insight into the transcriptional and post-transcriptional regulation of hepatocarcinogenesis. Targeted chemotherapies for TISC are in development as a means to overcome cellular resistance and mechanisms driving disease progression in liver cancer. © 2011 American Association for the Study of Liver Diseases.
Alliston T.,University of California at San Francisco |
Alliston T.,Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research
Current Osteoporosis Reports | Year: 2014
The ability of bone to resist fracture is determined by the combination of bone mass and bone quality. Like bone mass, bone quality is carefully regulated. Of the many aspects of bone quality, this review focuses on biological mechanisms that control the material quality of the bone extracellular matrix (ECM). Bone ECM quality depends upon ECM composition and organization. Proteins and signaling pathways that affect the mineral or organic constituents of bone ECM impact bone ECM material properties, such as elastic modulus and hardness. These properties are also sensitive to pathways that regulate bone remodeling by osteoblasts, osteoclasts, and osteocytes. Several extracellular proteins, signaling pathways, intracellular effectors, and transcription regulatory networks have been implicated in the control of bone ECM quality. A molecular understanding of these mechanisms will elucidate the biological control of bone quality and suggest new targets for the development of therapies to prevent bone fragility. © 2014 Springer Science+Business Media.
Smith L.K.,University of California at San Francisco |
Smith L.K.,Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research |
He Y.,Stanford University |
Park J.-S.,Stanford University |
And 28 more authors.
Nature Medicine | Year: 2015
Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.
Udeochu J.C.,University of California at San Francisco |
Shea J.M.,University of California at San Francisco |
Villeda S.A.,University of California at San Francisco |
Villeda S.A.,Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research
Clinical and Experimental Neuroimmunology | Year: 2016
Aging alters the functional integrity of the adult brain, driving cognitive impairments and susceptibility to neurodegenerative disorders in healthy individuals. In fact, aging remains the most dominant risk factor for Alzheimer's disease (AD). Recent findings have expanded our understanding of microglia function in the normal aging and AD brain, provoking an appreciation for microglia involvement in remodeling neuronal connections and maintaining brain integrity. This homeostatic function of microglia is achieved in part through the ability of microglia to interact extensively with and rapidly respond to changes in the brain microenvironment to enable adequate phenotypic transformations. Here, we discuss pro-inflammatory drivers of microglia transformation in aging and AD by focusing on the immune-modulatory functions of secreted factors, such as cytokines, complement factors and extracellular vesicles. We highlight the involvement of these secreted factors in aging and AD-associated cellular changes in microglia immune activation, surveillance function, and phagocytosis. Finally, we discuss how pro-inflammatory phenotypic changes associated with altered immune communication could both facilitate and exacerbate impairments in synaptic plasticity and cognitive function observed in the aged and AD brain. © 2016 The Authors. Clinical and Experimental Neuroimmunology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Society for Neuroimmunology.