Biomedical subjects

Jay M Edelberg

Publications and source records attributed to Jay M Edelberg.

28 records · Page 2Linked to original sources

PubMed2003

Adult cardiac stem cells--where do we go from here?

A potential treatment for cardiovascular disease involves the transplantation of a patient's bone marrow stem cells into the heart of that same patient. In order to maximize the potential benefits to select patient populations, the continued clinical development of this technology will require a comprehensive understanding of the role(s) of the transplanted cells in the repair of damaged heart tissue as well as an understanding of which types of cardiac injury can be repaired by this approach. The widespread application of cardiovascular stem cell therapies, however, will likely be based on pharmacological approaches to enhance the capacity of endogenous bone marrow stem cells to provide for the replacement of cardiac muscle and vascular cells after myocardial injury.

Animals↗

PubMed2003

Age-associated impairment in TNF-alpha cardioprotection from myocardial infarction.

Age-associated dysfunction in cardiac microvascular endothelial cells with impaired induction of cardioprotective platelet-derived growth factor (PDGF)-dependent pathways suggests that alterations in critical vascular receptor(s) may contribute to the increased severity of cardiovascular pathology in older persons. In vivo murine phage-display peptide library biopanning revealed a senescent decrease in cardiac microvascular binding of phage epitopes homologous to tumor necrosis factor-alpha (TNF-alpha), suggesting that its receptor(s) may be downregulated in older cardiac endothelial cells. Immunostaining demonstrated that TNF-receptor 1 (TNF-R1) density was significantly lower in the subendocardial endothelium of the aging murine heart. Functional studies confirmed the senescent dysregulation of TNF-alpha receptor pathways, demonstrating that TNF-alpha induced PDGF-B expression in cardiac microvascular endothelial cells of 4-mo-old, but not 24-mo-old, rats. Moreover, TNF-alpha mediated cardioprotective pathways were impaired in the aging heart. In young rat hearts, injection of TNF-alpha significantly reduced the extent of myocardial injury after coronary ligation: TNF-alpha, 7.9 +/- 1.9% left ventricular injury (n = 4) versus PBS, 16.2 +/- 7.9% (n = 10; P < 0.05). The addition of PDGF-AB did not augment the cardioprotective action of TNF-alpha. In myocardial infarctions of older hearts, however, TNF-alpha induced significant postcoronary occlusion mortality (TNF-alpha 80% vs. PBS 0%; n = 10 each, P < 0.05) that was reversed by the coadministration of PDGF-AB. Overall, these studies demonstrate that aging-associated alterations in TNF-alpha receptor cardiac microvascular pathways may contribute to the increased cardiovasular pathology of the aging heart. Strategies targeted at restoring TNF-alpha receptor-mediated expression of PDGF-B may improve cardiac microvascular function and provide novel approaches for treatment and possible prevention of cardiovascular disease in older individuals.

Aging↗

PubMed2003

Genetically engineered biologically based hemostatic bioassay.

Real-time direct measures of hemostatic parameters in vivo are required for optimizing the dynamic delivery of coagulation modifying pharmacotherapies. Typical sensors of physiologic functions in vivo, however, have only a restricted array of sensory inputs, and thus limited capacity to monitor thrombotic and hemostatic activity. To overcome this limitation we have developed a genetically engineered excitable cell line that can be potentially used for an implantable thrombin biosensor. Specifically, we have generated stem cell-derived cardiac myocyte aggregates overexpressing the human thrombin receptor, protease activated receptor-1 (PAR-1), which exploit the inherent electropotential input-output relationship of the cells to detect local changes in thrombin activity. In vitro, the signaling activity of PAR-1 cardiac myocytes was highly responsive to thrombin, inducing a sixfold increase in intracellular cAMP as compared with a twofold increase in control cells. In vivo, the engineered myocytes also detected alterations in local coagulation potential. Specifically, PAR-1 engineered cells implanted in vivo detected local increases in thrombin with a doubling in chronotropic activity compared with a 50% increase in control aggregates. Overall these studies demonstrate the potential of genetic engineering to expand the physiologic signals recognized by excitable cells, and may facilitate the translation of this approach for the real-time monitoring of hemostatic function in vivo.

Animals↗

PubMed2003

Translation of PDGF cardioprotective pathways.

Vascular function in the aging heart is impaired and may underlie the increased morbidity and mortality associated with ischemic heart disease in older individuals. This vascular dysfunction is due, in part, to impairment of platelet derived growth factor (PDGF)-mediated pathways in senescent cardiac microvascular endothelial cells. Restoration of these pathways by intramyocardial injection of growth factor transiently rescues senescent cardiac angiogenesis. Longer-term reconstitution can be achieved experimentally by transplantation of young bone marrow-derived stem cells to promote senescent cardiac angiogenic function in the murine host. Moreover, enhancement of PDGF pathways is cardioprotective, markedly reducing the extent of myocardial injury following coronary occlusion. The clinical translation of these findings for treatment of ischemic heart diseases must overcome the limitation of the proatherosclerotic actions of PDGF, as well as the generation of autologous stem/precursor cell approaches, for the aging cardiovascular system. Strategies targeting growth factor and/or stem-cell homing to gene products downstream of PDGF in the cardiac microvasculature may provide positive feedback loops to enhance cardiac angiogenesis and protection from myocardial infarction and may offer a foundation for developing novel therapies for the prevention and treatment of cardiovascular disease associated with aging.

Aging↗

PubMed2002

Auto repair on the aging stem cell superhighway.

Adult bone marrow stem cells offer the potential for rejuvenation of diseased or damaged tissues and organs. The greatest need for such a treatment in older individuals is to counter age-associated predisposition to cardiovascular diseases. Unfortunately, changes in senescent vascular function might limit the recruitment of bone marrow-derived precursor cells. In order to provide the patient with the conduits required to deliver bone marrow cells to damaged tissues, it is essential to develop strategies to overcome these limitations. This effort will require novel approaches to reverse aging-associated vascular dysfunction, including reharnessing the potential of stem cells from the aging bone marrow for vascular repair.

Animals↗

PubMed2002

Young adult bone marrow-derived endothelial precursor cells restore aging-impaired cardiac angiogenic function.

Delivery of young bone marrow-derived stem cells offers a novel approach for restoring the impaired senescent cardiac angiogenic function that may underlie the increased morbidity and mortality associated with ischemic heart disease in older individuals. Recently, we reported that alterations in endothelial cells of the aging heart lead to a dysregulation in the cardiac myocyte platelet-derived growth factor (PDGF)-B-induced paracrine pathway, which contributes to impaired cardiac angiogenic function. Based on these results, we hypothesized that cellular restoration of the PDGF pathway by bone marrow-derived endothelial precursor cells (EPCs) could reverse the aging-associated decline in angiogenic activity. In vitro studies revealed that young murine (3-month-old) bone marrow-derived EPCs recapitulated the cardiac myocyte-induced expression of PDGF-B, whereas EPCs from the bone marrow of aging mice (18-month-old) did not express PDGF-B when cultured in the presence of cardiac myocytes. Transplantation of young, but not old, genetically marked syngeneic bone marrow cells into intact, unirradiated aging mice that populated the endogenous senescent murine bone marrow incorporated into the neovasculature of subsequently transplanted syngeneic neonatal myocardium. Moreover, the young bone marrow-derived EPCs restored the senescent host angiogenic PDGF-B induction pathway and cardiac angiogenesis, with graft survival and myocardial activity in the aging murine host (cardiac allograft viability: 3-month-old controls, 8/8; 18-month-old controls, 1/8; 18-month-old donors receiving bone marrow from 3-month-old mice, 15/16; or 18-month-old mice, 0/6; P<0.05). These results may offer a foundation for the development of novel therapies for the prevention and treatment of cardiovascular disease associated with aging.

Aging↗

PubMed2002

Loss of SR-BI expression leads to the early onset of occlusive atherosclerotic coronary artery disease, spontaneous myocardial infarctions, severe cardiac dysfunction, and premature death in apolipoprotein E-deficient mice.

Murine models of atherosclerosis, such as the apolipoprotein E (apoE) or the LDL receptor knockout mice, usually do not exhibit many of the cardinal features of human coronary heart disease (CHD), eg, spontaneous myocardial infarction, severe cardiac dysfunction, and premature death. Here we show that mice with homozygous null mutations in the genes for both the high density lipoprotein receptor SR-BI and apoE (SR-BI/apoE double knockout [dKO] mice) exhibit morphological and functional defects with similarities to those seen in human CHD. When fed a standard chow diet, these hypercholesterolemic animals developed significant atherosclerotic lesions in the aortic sinus as early as 4 to 5 weeks after birth. We now show that they also exhibited extensive lipid-rich coronary artery occlusions and spontaneously developed multiple myocardial infarctions and cardiac dysfunction (eg, enlarged hearts, reduced ejection fraction and contractility, and ECG abnormalities). Their coronary arterial lesions, which were strikingly similar to human atherosclerotic plaques, exhibited evidence of cholesterol clefts and extensive fibrin deposition, indicating hemorrhage and clotting. All of the dKO mice died by 8 weeks of age (50% mortality at 6 weeks). Thus, SR-BI/apoE dKO mice provide a new murine model for CHD and may help better define the role of lipoprotein metabolism and atherosclerosis in the pathogenesis of myocardial infarction and cardiac dysfunction. Furthermore, these animals may be useful for preclinical testing of potential genetic and/or pharmacological therapies for CHD.

Age of Onset↗

PubMed2002

Platelet-derived growth factor-AB limits the extent of myocardial infarction in a rat model: feasibility of restoring impaired angiogenic capacity in the aging heart.

BACKGROUND: Compared with younger patients, myocardial infarction in the elderly has been associated with less favorable clinical outcomes, which may be attributable to a decline in angiogenic capacity in the aging heart. METHODS AND RESULTS: To test the hypothesis that the functional phenotype of cardiac microvascular endothelial cells is maintained partly by a cardiac myocyte platelet-derived growth factor (PDGF)-B-induced paracrine pathway, we conducted in vitro studies with murine cardiac cells. These studies demonstrated that unlike young endothelial cells, endothelial cells of the aging heart do not express PDGF-B when cultured in the presence of cardiac myocytes. The functional significance of this endothelial dysregulation was assessed with an ex vivo pinnal cardiac allograft model to demonstrate that senescent cardiac angiogenic activity was depressed (2 of 17 allografts were viable in 18-month-old mice versus 19 of 20 in 3-month-old mice; P<0.01). PDGF-AB pretreatment specifically restored the viability of the cardiac allografts in the aging hosts (13 of 13 allografts were viable; P<0.01 versus 18-month-old controls). Finally, in vivo studies in rat hearts demonstrated that pretreatment by intramyocardial delivery of PDGF-AB promotes angiogenesis and minimizes the extent of myocardial infarction in the aging hearts after coronary ligation (myocardial infarction size: 10.0 +/- 7.0% of left ventricular area in PDGF pretreatment [n=7] versus 17.6 +/- 5.6% in control [n=5] groups; P<0.03). CONCLUSION: Aging hearts have impaired angiogenic function as a result of depressed PDGF-B production. Restoration of the dysregulated endothelial PDGF-mediated angiogenic pathway in the aging heart reverses the senescent impairment in cardioprotective angiogenic function and offers a foundation for developing novel therapies for cardiovascular disease in older individuals.

Age Factors↗

PubMed2002

Enhanced myocyte-based biosensing of the blood-borne signals regulating chronotropy.

Biosensors play a critical role in the real-time determination of relevant functional physiological needs. However, typical in vivo biosensors only approximate endogenous function via the measurement of surrogate signals and, therefore, may often lack a high degree of dynamic fidelity with physiological requirements. To overcome this limitation, we have developed an excitable tissue-based implantable biosensor approach, which exploits the inherent electropotential input-output relationship of cardiac myocytes to measure the physiological regulatory inputs of chronotropic demand via the detection of blood-borne signals. In this study, we report the improvement of this application through the modulation of host-biosensor communication via the enhancement of vascularization of chronotropic complexes in mice. Moreover, in an effort to further improve translational applicability as well as molecular plasticity, we have advanced this approach by employing stem cell-derived cardiac myocyte aggregates in place of whole cardiac tissue. Overall, these studies demonstrate the potential of biologically based biosensors to predict endogenous physiological dynamics and may facilitate the translation of this approach for in vivo monitoring.

Animals↗

PubMedDate not supplied

Age-related differences in repair of dermal wounds and myocardial infarcts attenuate during the later stages of healing.

BACKGROUND: It is unclear whether delays in wound repair due to the age of the host persist into the later stages of healing. Late stage healing of dermal wounds and myocardial infarcts in rodents was examined to determine if aged animals "catch up" to their younger counterparts. MATERIALS AND METHODS: Excisional dermal wounds (5 mm) were made by punch biopsy and myocardial infarctions were produced by ligation of the left anterior descending coronary artery in young and aged mice and rats, respectively. Dermal wounds at day 11 and myocardial infarctions at day 14 were analyzed for wound area, angiogenesis, deposition of basement membrane proteins, and remodeling of collagen. RESULTS: Analyses demonstrated that wound areas, the deposition of basement membrane proteins and angiogenic responses were similar in young and aged rodents at late stages of wound repair. The dermal wounds of young mice had larger quantities of mature, compacted collagen fibers relative to aged mice, but immature collagen fibers predominated in myocardial infarcts in both young and aged rats. CONCLUSION: These results show that, with the exception of dermal collagen remodeling, aged animals catch up to their young counterparts with respect to many features of tissue repair. Consequently, therapies that target age-related deficiencies in healing will be most effective when administered shortly after the initial insult.

Aging↗