A29. STEM CELLS: WHO ARE YOU, HOW CAN YOU HELP ME AND WHAT DO YOU NEED?, 2011
Tissue fibrosis is a common pathological outcome of chronic disease that markedly impairs organ f... more Tissue fibrosis is a common pathological outcome of chronic disease that markedly impairs organ function leading to morbidity and mortality. In the lung, idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Here, we show that alveolar type 2 (AT2) stem cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence. We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of epithelial stem cells serves as a proximal driver of Tgfβ activation and progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation, senescence, or downstream Tgfβ activation, block fibrogenesis. .
ABSTRACT Stem cells are emerging as a therapeutic modality in various inflammatory disease states... more ABSTRACT Stem cells are emerging as a therapeutic modality in various inflammatory disease states. A number of ongoing randomized phase I/II clinical trials are evaluating the effects of allogeneic mesenchymal stem cell (MSC) infusion in patients with multiple sclerosis, graft-versus-host disease, Crohn’s disease, and severe chronic myocardial ischemia. MSCs are also being considered as a potential therapy in patients with inflammatory lung diseases. Several studies, including our own, have demonstrated compelling benefits from the administration of MSCs in animal models of lung injury. These studies are leading to growing interest in the therapeutic use of MSCs in inflammatory lung diseases. In this chapter, we describe the use of animal models and how the immunoregulatory effects of MSCs can confer substantial protection in the setting of lung diseases such as acute lung injury, chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. In addition, we identify emerging areas for MSC-based therapies in modulating oxidative stress and in attenuating acute lung injury in the alcoholic host. KeywordsMesenchymal stem cells-Asthma-Acute lung injury-Transplant-Oxidative stress
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2009
A GING is characterized as a progressive decline in tissue and organ function, accompanied by inc... more A GING is characterized as a progressive decline in tissue and organ function, accompanied by increased free radical damage (1), mitochondrial dysfunction (2), endocrine imbalance (3), and genome instability (4). Aging is also associated with a decline in immunity described as immunosenescence, a well-recognized phenomenon in humans and animals (5). Especially relevant to the fi brotic response, normal aging is associated with a shift in T lymphocytes from a predominantly T-helper (T H) 1 phenotype to a predominantly T H 2 phenotype by increasing the production of interleukin (IL)-4, IL-5, IL-10, and IL-13, which are responsible for strong profi brotic response and transforming growth factor (TGF)-b 1 production. Several recent studies have documented differences in bone marrow-derived stem cell (BMDMSC) performance between young and old animals. Administration of endothelial progenitor cells from young, but not from old, mice restored pathways critical for cardiac angiogenesis in senescent mice without prior bone marrow (BM) suppression (6). Rauscher and associates (7) demonstrated that chronic treatment with BM-derived progenitor cells from young nonatherosclerotic ApoE-/mice prevented the progression of atherosclerosis in aged ApoE-/mice despite persistent hypercholesterolemia. In a remarkable study, Conboy and coworkers (8) demonstrated that heterochronic parabiotic mice (two mice, one old and one young, surgically joined with shared circulatory systems) restored age-related loss of stem cell capacity in muscle, blood, and liver in the older member of the pair. The senescence-accelerated mouse (SAM) is a commonly used model for studying physiological and pathological responses during aging. The SAM strain is derived from the AKR/J strain of mice by continuous brother-sister mating selected for a phenotype toward either accelerated senescence or resistance senescence. There are nine major senescenceaccelerated prone mouse (SAMP, P) strains and three major senescence-accelerated resistant mouse (SAMR, R) strains (9). The P8 strain of SAMP (SAMP8) shows spontaneous learning and memory defects at 2 months of age, which deteriorate with aging (10). SAMP8 mice are also prone to amyloid deposition, cataracts, osteoporosis, degenerative joint disease, decreased immune responses, increased lordokyphosis, and various other hallmarks of aging (11). Although both the incidence and the severity of acute lung injury and fi brotic lung disease increase with age, there is relatively little known about the mechanisms by which aging increases susceptibility to these lung diseases. Research from our lab and others has shown that BMDMSCs play a critical role in lung injury and fi brosis. We hypothesize that aging affects the response of BMDMSCs to lung injury. In addition to addressing a fundamental biologic mechanism, the study provides a rationale for interventions that can be tested in animal models and could eventually be applicable to humans.
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2005
Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease of unknown etiology. ... more Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease of unknown etiology. A viral pathogenesis in IPF has been suggested since >95% of IPF patients have evidence of chronic pulmonary infection with one or more herpesviruses. To determine whether pulmonary infection with herpesvirus can cause lung fibrosis, we infected mice with the murine γ-herpesvirus 68 (MHV68). Because IPF patients have a T helper type 2 (Th2) pulmonary phenotype, we used IFN-γR−/−, a strain of mice biased to develop Th2 responses. Chronic MHV68 infection of IFN-γR−/− mice resulted in progressive deposition of interstitial collagen as shown by light and electron microscopy. A significant decrease in tidal volume paralleled the collagen deposition. Five features typically seen in IPF, increased transforming growth factor-β expression, myofibroblast transformation, production of Th2 cytokines, hyperplasia of type II cells, and increased expression of matrix metalloproteinase-7, were also p...
ObjectiveAge‐related changes in the larynx lead to significant voice impairment and reduced quali... more ObjectiveAge‐related changes in the larynx lead to significant voice impairment and reduced quality of life. There is a need for aged animal models that have practical generation times to study the fundamental changes and new therapeutics for the aging voice. The senescence accelerated prone mouse strain (SAMP) animals experience rapid aging without any experimental manipulation. The main objective of this study was to demonstrate the use of senescence accelerated mice to study aging in the larynx.Study DesignMurine model.SettingDepartment of Animal Resources, Emory University.Subjects and MethodsLarynges from five senescence accelerated prone mice, five normal aging senescence resistant mice, and five C57BL/6 mice were harvested and processed for paraffin sections. Histomorphometry was performed for assessment of collagen and hyaluronic acid distribution. In addition, frozen laryngeal tissue was harvested for transcriptional and translational assessment of collagen‐1, using real‐ti...
A29. STEM CELLS: WHO ARE YOU, HOW CAN YOU HELP ME AND WHAT DO YOU NEED?, 2011
Tissue fibrosis is a common pathological outcome of chronic disease that markedly impairs organ f... more Tissue fibrosis is a common pathological outcome of chronic disease that markedly impairs organ function leading to morbidity and mortality. In the lung, idiopathic pulmonary fibrosis (IPF) is an insidious and fatal interstitial lung disease associated with declining pulmonary function. Here, we show that alveolar type 2 (AT2) stem cells isolated from IPF lung tissue exhibit characteristic transcriptomic features of cellular senescence. We used conditional loss of Sin3a in adult mouse AT2 cells to initiate a program of p53-dependent cellular senescence, AT2 cell depletion, and spontaneous, progressive pulmonary fibrosis. We establish that senescence rather than loss of epithelial stem cells serves as a proximal driver of Tgfβ activation and progressive fibrosis and show that either genetic or pharmacologic interventions targeting p53 activation, senescence, or downstream Tgfβ activation, block fibrogenesis. .
ABSTRACT Stem cells are emerging as a therapeutic modality in various inflammatory disease states... more ABSTRACT Stem cells are emerging as a therapeutic modality in various inflammatory disease states. A number of ongoing randomized phase I/II clinical trials are evaluating the effects of allogeneic mesenchymal stem cell (MSC) infusion in patients with multiple sclerosis, graft-versus-host disease, Crohn’s disease, and severe chronic myocardial ischemia. MSCs are also being considered as a potential therapy in patients with inflammatory lung diseases. Several studies, including our own, have demonstrated compelling benefits from the administration of MSCs in animal models of lung injury. These studies are leading to growing interest in the therapeutic use of MSCs in inflammatory lung diseases. In this chapter, we describe the use of animal models and how the immunoregulatory effects of MSCs can confer substantial protection in the setting of lung diseases such as acute lung injury, chronic obstructive pulmonary disease, asthma, and pulmonary hypertension. In addition, we identify emerging areas for MSC-based therapies in modulating oxidative stress and in attenuating acute lung injury in the alcoholic host. KeywordsMesenchymal stem cells-Asthma-Acute lung injury-Transplant-Oxidative stress
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 2009
A GING is characterized as a progressive decline in tissue and organ function, accompanied by inc... more A GING is characterized as a progressive decline in tissue and organ function, accompanied by increased free radical damage (1), mitochondrial dysfunction (2), endocrine imbalance (3), and genome instability (4). Aging is also associated with a decline in immunity described as immunosenescence, a well-recognized phenomenon in humans and animals (5). Especially relevant to the fi brotic response, normal aging is associated with a shift in T lymphocytes from a predominantly T-helper (T H) 1 phenotype to a predominantly T H 2 phenotype by increasing the production of interleukin (IL)-4, IL-5, IL-10, and IL-13, which are responsible for strong profi brotic response and transforming growth factor (TGF)-b 1 production. Several recent studies have documented differences in bone marrow-derived stem cell (BMDMSC) performance between young and old animals. Administration of endothelial progenitor cells from young, but not from old, mice restored pathways critical for cardiac angiogenesis in senescent mice without prior bone marrow (BM) suppression (6). Rauscher and associates (7) demonstrated that chronic treatment with BM-derived progenitor cells from young nonatherosclerotic ApoE-/mice prevented the progression of atherosclerosis in aged ApoE-/mice despite persistent hypercholesterolemia. In a remarkable study, Conboy and coworkers (8) demonstrated that heterochronic parabiotic mice (two mice, one old and one young, surgically joined with shared circulatory systems) restored age-related loss of stem cell capacity in muscle, blood, and liver in the older member of the pair. The senescence-accelerated mouse (SAM) is a commonly used model for studying physiological and pathological responses during aging. The SAM strain is derived from the AKR/J strain of mice by continuous brother-sister mating selected for a phenotype toward either accelerated senescence or resistance senescence. There are nine major senescenceaccelerated prone mouse (SAMP, P) strains and three major senescence-accelerated resistant mouse (SAMR, R) strains (9). The P8 strain of SAMP (SAMP8) shows spontaneous learning and memory defects at 2 months of age, which deteriorate with aging (10). SAMP8 mice are also prone to amyloid deposition, cataracts, osteoporosis, degenerative joint disease, decreased immune responses, increased lordokyphosis, and various other hallmarks of aging (11). Although both the incidence and the severity of acute lung injury and fi brotic lung disease increase with age, there is relatively little known about the mechanisms by which aging increases susceptibility to these lung diseases. Research from our lab and others has shown that BMDMSCs play a critical role in lung injury and fi brosis. We hypothesize that aging affects the response of BMDMSCs to lung injury. In addition to addressing a fundamental biologic mechanism, the study provides a rationale for interventions that can be tested in animal models and could eventually be applicable to humans.
American Journal of Physiology-Lung Cellular and Molecular Physiology, 2005
Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease of unknown etiology. ... more Idiopathic pulmonary fibrosis (IPF) is a progressive, fibrotic lung disease of unknown etiology. A viral pathogenesis in IPF has been suggested since >95% of IPF patients have evidence of chronic pulmonary infection with one or more herpesviruses. To determine whether pulmonary infection with herpesvirus can cause lung fibrosis, we infected mice with the murine γ-herpesvirus 68 (MHV68). Because IPF patients have a T helper type 2 (Th2) pulmonary phenotype, we used IFN-γR−/−, a strain of mice biased to develop Th2 responses. Chronic MHV68 infection of IFN-γR−/− mice resulted in progressive deposition of interstitial collagen as shown by light and electron microscopy. A significant decrease in tidal volume paralleled the collagen deposition. Five features typically seen in IPF, increased transforming growth factor-β expression, myofibroblast transformation, production of Th2 cytokines, hyperplasia of type II cells, and increased expression of matrix metalloproteinase-7, were also p...
ObjectiveAge‐related changes in the larynx lead to significant voice impairment and reduced quali... more ObjectiveAge‐related changes in the larynx lead to significant voice impairment and reduced quality of life. There is a need for aged animal models that have practical generation times to study the fundamental changes and new therapeutics for the aging voice. The senescence accelerated prone mouse strain (SAMP) animals experience rapid aging without any experimental manipulation. The main objective of this study was to demonstrate the use of senescence accelerated mice to study aging in the larynx.Study DesignMurine model.SettingDepartment of Animal Resources, Emory University.Subjects and MethodsLarynges from five senescence accelerated prone mice, five normal aging senescence resistant mice, and five C57BL/6 mice were harvested and processed for paraffin sections. Histomorphometry was performed for assessment of collagen and hyaluronic acid distribution. In addition, frozen laryngeal tissue was harvested for transcriptional and translational assessment of collagen‐1, using real‐ti...
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