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Biomedical subjects

Doris A Taylor

Publications and source records attributed to Doris A Taylor.

At least 19 recordsLinked to original sources
PubMed2007

The adult human heart as a source for stem cells: repair strategies with embryonic-like progenitor cells.

Adequate cell-based repair of adult myocardium remains an elusive goal because most cells that are used cannot generate mature myocardium sufficient to promote large functional improvements. Embryonic stem cells can generate both mature cardiocytes and vasculature, but their use is hampered by associated teratoma formation and the need for an allogeneic source. The detection of sca-1(+), c-kit(+), or isl-1(+) cardiac precursors and the creation of cardiospheres from adult heart tissues suggest that a persistent population of immature progenitor cells is present in the mature myocardium. These cell populations probably represent stages along a continuum of cardiac stem cell development and differentiation. We report isolation from ventricle of uncommitted cardiac progenitor cells, which appear to resemble the more immature, common pool of embryonic lateral plate mesoderm progenitors that yield both myocardial and endocardial cells during normal cardiac development. Under controlled in vitro conditions and in vivo, these cells can differentiate into endothelial, smooth muscle, and cardiomyocyte lineages and can be isolated and expanded to clinically relevant numbers from adult rat myocardial tissue. In this article, we discuss the potential for autologous repair or even cardiac regeneration with cells that follow a developmental pathway similar to embryonic cardiac precursors but without the inherent limitations associated with undifferentiated embryonic stem cells.

Adult↗
PubMed2006

Systolic contraction within aneurysmal rabbit myocardium following transplantation of autologous skeletal myoblasts.

OBJECTIVE: Transplantation of autologous skeletal myoblasts (SKMB) into infarcted heart (or cellular cardiomyoplasty, CCM) augments myocardial performance in animal models of myocardial infarction. However, the effect of CCM in the setting of ventricular aneurysm has not been evaluated. This study analyzes the effects of transplanted SKMB on regional wall motion in a rabbit model of postinfarct ventricular aneurysm. We hypothesize that CCM, performed early after myocardial infarction, prevents the progression of dyskinetic wall motion. METHODS: Twenty-six rabbits underwent apical left ventricular cryoinfarction and soleus muscle biopsy for in vitro isolation of skeletal myoblasts. At 2 weeks postinfarct, the presence of ventricular aneurysm was detected in 23/26 animals by sonomicrometry and micromanometry. Seventeen of 23 animals were randomized to receive either 108 autologous myoblasts (CCM) or vehicle. Regional stroke work, percent systolic shortening, and synchronicity of regional wall motion were determined prior to, and four weeks following, injection (CCM; n = 9; vehicle, n = 8). Wall motion was evaluated under baseline and stress (dobutamine, 10 (g/kg/min) conditions. Six animals did not undergo randomization, but their hearts were used to measure the size of infarction. RESULTS: Four weeks following treatment of animals with ventricular aneurysm, systolic contractile activity was present in most animals treated with myoblasts but in none treated with vehicle (5/7 versus 0/6, respectively, P < 0.05). Dobutamine tended to accentuate the differences seen at baseline between the groups. CONCLUSIONS: This study demonstrates a high incidence of systolic contractile activity in a previously aneurysmal region of myocardium following CCM and may represent a novel therapy for the prevention and treatment of postinfarct aneurysm.

Animals↗
PubMed2006

Circulating endothelial progenitor cells predict coronary artery disease severity.

BACKGROUND: Circulating endothelial progenitor cells (EPCs) may play an important role in the body's defense against atherosclerosis. Previous studies have shown an association between EPC numbers and the presence of traditional coronary artery disease (CAD) risk factors. The relationship between EPC numbers and the severity of atherosclerosis is, however, not known. METHODS: EPC counts were measured by quantitative cell culture in 122 patients undergoing diagnostic cardiac catheterization. The association between patients' EPC count and the presence of multivessel CAD and traditional cardiac risk factors was assessed using logistic regression analysis. RESULTS: The median age of the study population was 58 years; 37% had multivessel CAD, 29% had diabetes, and 14% had myocardial infarction this admission. EPC counts did not vary significantly with most established cardiac risk factors but were lower in diabetics versus nondiabetics and trended toward lower numbers in older patients. EPC count was the second strongest predictor of multivessel CAD, after patient age. Patients with multivessel disease had significantly lower EPC counts than those without (median, 3 vs 13; P < .0088). For every 10 colony forming unit increase in EPCs, a patient's likelihood for multivessel CAD declined by 20% (P < .001). CONCLUSION: This study demonstrates an inverse relationship between circulating EPCs and CAD severity, independent of traditional risk factors. If confirmed in ongoing studies, this may represent an important new diagnostic and therapeutic target for coronary disease treatment.

Aged↗
PubMed2006

From cardiac repair to cardiac regeneration--ready to translate?

Cardiovascular disease is a major public health challenge in the western world. Mortality of acute events has improved, but more patients develop HF--a condition affecting up to 22 million people worldwide. Cell transplantation is the first therapy to attempt replacement of lost cardiomyocytes and vasculature to restore lost contractile function. Since the first reported functional repair after injection of autologous skeletal myoblasts into the injured heart in 1998, a variety of cell types have been proposed for transplantation in different stages of cardiovascular disease. Fifteen years of preclinical research and the rapid move into clinical studies have left us with promising results and a better understanding of cells as a potential clinical tool. Cell-based cardiac repair has been the first step, but cardiac regeneration remains the more ambitious goal. Promising new cell types and the rapidly evolving concept of adult stem and progenitor cell fate may enable us to move towards regenerating viable and functional myocardium. Meeting a multidisciplinary consensus will be required to translate these findings into safe and applicable clinical tools.

Animals↗
PubMed2005

Autologous skeletal myoblast transplantation improved hemodynamics and left ventricular function in chronic heart failure dogs.

BACKGROUND: Previous studies have suggested that autologous skeletal myoblast transplantation (ASMT) improves left ventricular (LV) function in small animals after myocardial infarction. We tested the effects of ASMT on hemodynamics, LV function and remodeling in coronary microembolization-induced chronic heart failure (CHF) in conscious dogs. METHODS: Nineteen dogs were continuously instrumented with LV pressure sensors and mid-myocardial sonomicrometry crystals for dP/dt(max) and LV volume determination. Each dog underwent baseline assessment in a conscious state. CHF (20% to 30% reduction in dP/dt(max) and LV end-diastolic pressure >16 mm Hg) was created by daily coronary microembolizations via a continuously implanted coronary catheter. Skeletal muscle biopsy was performed and myoblasts were isolated and expanded. Then 2.7 x 10(8) to 8.3 x 10(8) myoblasts were injected into the infarcted region of 11 dogs after establishment of CHF. Saline injection (sham) was performed in 8 control dogs. Animals were evaluated every 2 weeks for up to 10 weeks. Global ejection fraction was determined by echocardiography. The end-systolic pressure-end-systolic volume relationship (ESPVR) was analyzed by the Sonomicrometic system. RESULTS: Compared with saline injection, ASMT significantly increased dP/dt(max) (105 +/- 9% vs 97 +/- 7%, values were expressed as percentage change from baseline CHF, p = 0.013) and ejection fraction (46 +/- 3% vs 40 +/- 2%, p = 0.034) at 10 weeks after myoblast transplantation. There was a significant leftward and upward shift of the ESPVR back toward normal at 10 weeks after myoblast transplantation (p = 0.034). Three animals labeled with BrdU myoblasts showed no histologic evidence of viable engraftment. CONCLUSIONS: ASMT provided mild improvements in hemodynamics and LV function and reduced LV remodeling in conscious dogs with CHF.

Animals↗
PubMed2005

Functional assessment of myoblast transplantation for cardiac repair with magnetic resonance imaging.

BACKGROUND: Contraction of transplanted myoblasts and their effects on function and remodeling after myocardial infarction remain controversial. AIM: We used magnetic resonance imaging (MRI) to study wall thickening and left ventricular (LV) function and geometry after myoblast transplantation. METHODS AND RESULTS: Three weeks after cryo-infarction rabbits were randomized to receive an injection of approximately 2 x 10(8) myoblasts (n=8) or medium (n=9) into the scar. Cine MRI and contrast enhanced (ce) MRI images were acquired before injection (baseline) and 4 weeks later (endpoint). Regional wall thickening was measured at the site of transmural hyperenhancement. In the control group, regional wall thickening decreased to -15.3+/-8.6% at baseline, which further decreased to -18.3+/-5.7% at endpoint. Further, end-diastolic volume increased from 3.96+/-0.27 to 5.00+/-0.46 ml and end-systolic volume from 2.23+/-0.19 to 2.96+/-0.30 ml (both P<0.05 vs. baseline), which was accompanied by increased LV wall volumes (P<0.05 vs. baseline). In contrast, myoblast transplantation increased regional wall thickening from -11.9+/-15.9% at baseline to 26.9+/-17.0% (P<0.05 vs. control), which resulted in significantly improved two-dimensional ejection fractions at the infarct level and prevented the increase in end-diastolic and end-systolic volumes and wall volume. CONCLUSION: Intracardiac myoblast transplantation after myocardial infarction improves regional wall thickening and prevents progressive left ventricular remodeling.

Animals↗
PubMed2005

Intracardiac transplantation of a mixed population of bone marrow cells improves both regional systolic contractility and diastolic relaxation.

BACKGROUND: Pre-clinical and clinical studies suggest that transplantation of bone marrow-derived stem cells can improve global cardiac function. However, no quantitative assessment of regional systolic contraction and correlation with phenotype has been made. Therefore, we used our model of cryoinfarcted rabbit myocardium for intracardiac transplantation of a mixed population of bone marrow-derived cells and assessed both regional function and myogenic conversion of the cells. METHODS: Nineteen New Zealand white rabbits underwent cryoinjury of the left ventricle. Autologous bone marrow (BM) cells were expanded in vitro. After 2 weeks, either 1 x 10(8) mixed BM-derived progenitor cells (BM group, n = 11) or vehicle (control group, n = 8) were injected into the cryoinjured region. Regional systolic function was measured using micromanometry and sonomicrometry before and 4 weeks after cell injection; cell phenotype was evaluated histologically. RESULTS: All animals in the BM group significantly improved both systolic shortening (0.11 +/- 0.7 vs -0.05 +/- 0.05 mm in the control group, p < 0.05) and regional stroke work when compared with control (9.6 +/- 2.4 vs -1.2 +/- 1.2 mm . mm Hg, p < 0.003). In addition, the BM group had improved global diastolic function, as measured by minimum dP/dt and end-diastolic pressure. On histologic assessment, BM cells differentiated toward a myogenic phenotype. CONCLUSIONS: Transplanting a mixed population of marrow-derived cells that can adopt a myogenic phenotype improves regional contractility and diastolic relaxation after myocardial infarction.

Animals↗
PubMed2005

Cell therapy for heart failure--muscle, bone marrow, blood, and cardiac-derived stem cells.

Heart failure (HF) affects a rapidly growing population of patients. Despite improvements in the understanding and therapy of many stages of cardiovascular disease, there has been little progress in treating HF. In the late-stage disease, current options are cardiac transplantation and mechanical support--options that are limited to a small patient collective. The ischemically injured failing heart lacks contractile myocardium, functional vasculature, and electrical integrity, which has made treatment of the underlying injury untenable in the past. Restoring all of these components seems an overwhelming challenge. Yet, the concept of cell therapy--tissue repair by transplantation of stem and progenitor cells--has opened new potential options for patients with heart failure. Skeletal myoblasts, bone marrow, and blood-derived stem cells have all shown considerable myogenic and angiogenic potential in vitro and have rapidly moved from bench to bedside. A number of nonrandomized, non-placebo-controlled safety and feasibility studies have been reported and now double-blinded randomized controlled trials are underway. Despite this rapid clinical pace, the exact mechanisms underlying the functional benefits of different cell types are not well understood. Instead, multiple similar mechanism have been ascribed to virtually every cell type. Thus, while the field is exciting and offers unheralded promise to treat patients with CVD, we must proceed with due diligence and caution. Only a deep understanding of the benefits versus the risks, and the mechanisms involved in cell-mediated cardiac repair, will allow us to design clinically valuable tools and fulfill the potential of this exciting 21st century approach to treating cardiovascular disease.

Animals↗
PubMed2004

Engineering skeletal myoblasts: roles of three-dimensional culture and electrical stimulation.

Immature skeletal muscle cells, or myoblasts, have been used in cellular cardiomyoplasty in attempts to regenerate cardiac muscle tissue by injection of cells into damaged myocardium. In some studies, muscle tissue within myoblast implant sites may be morphologically similar to cardiac muscle. We hypothesized that identifiable aspects of the cardiac milieu may contribute to growth and development of implanted myoblasts in vivo. To test this hypothesis, we designed a novel in vitro system to mimic some aspects of the electrical and biochemical environment of native myocardium. This system enabled us to separate the three-dimensional (3-D) electrical and biochemical signals that may be involved in myoblast proliferation and plasticity. Myoblasts were grown on 3-D polyglycolic acid mesh scaffolds under control conditions, in the presence of cardiac-like electrical current fluxes, or in the presence of culture medium that had been conditioned by mature cardiomyocytes. Cardiac-like electrical current fluxes caused increased myoblast number in 3-D culture, as determined by DNA assay. The increase in cell number was due to increased cellular proliferation and not differences in apoptosis, as determined by proliferating cell nuclear antigen and TdT-mediated dUTP nick-end labeling. Cardiomyocyte-conditioned medium also significantly increased myoblast proliferation. Expression of transcription factors governing differentiation along skeletal or cardiac lineages was evaluated by immunoblotting. Although these assays are qualitative, no changes in differentiation state along skeletal or cardiac lineages were observed in response to electrical current fluxes. Furthermore, from these experiments, conditioned medium did not appear to alter the differentiation state of skeletal myoblasts. Hence, cardiac milieu appears to stimulate proliferation but does not affect differentiation of skeletal myoblasts.

Animals↗
PubMed2004

Video-assisted thoracoscopic transplantation of myoblasts into the heart.

PURPOSE: Currently, cells are transplanted into injured myocardium either through thoracotomy for open surgical delivery or through catheterization for endoventricular or intracoronary delivery; both methods have limitations. Open surgical delivery limits the potential patient population, whereas catheter-based delivery limits the ability to visualize the injection site and confirm delivery of the cells to the appropriate region. In this study, we examine the feasibility of cell transplantation into myocardium using a minimally invasive thoracoscopic approach. DESCRIPTION: Seven swine underwent thoracoscopic cell transplantation. Using a prototype injection device, approximately 10 million myoblasts were injected into the anterior, lateral, posterior, and apical regions of myocardium. Animals were recovered up to 7 days, and after euthanasia, hearts were explanted for histology. EVALUATION: All seven swine had successful delivery of myoblasts into the defined injection sites, as confirmed by analysis of an operative video, magnetic resonance imaging of iron-oxide-labeled cells, and histologic examination. CONCLUSIONS: Thoracoscopic cellular cardiomyoplasty is feasible and allows the surgeon the benefits of direct visualization of the cell injection while minimizing morbidity associated with open cell delivery.

Animals↗
PubMed2004

Cell-based myocardial repair: how should we proceed?

Cell-based myocardial repair and regeneration heralds a new frontier in the treatment of cardiovascular disease. It provides an unprecedented opportunity to treat the underlying loss of cardiomyocytes that occurs after myocardial injury and that results in the cascade of events leading to heart failure. Yet, even as it progresses to the clinic, much remains to be understood about this technology. For example, controversies exist over the specific cells to be used, the cell dosages needed, how cells will impact the electrical activity of the myocardium, and even whether transplanted cells can actually improve myocardial function. We can perhaps answer these questions more quickly and more effectively - and thus benefit patients more rapidly - if we learn from the successes and failures of our gene therapy colleagues and take a prudent, step-wise approach from bench to bedside. To do so, we need only to promise what we can deliver, to do careful science, and then to deliver well on our promises. Although cellular cardiomyoplasty (cell transplantation for cardiac repair) shows great early clinical promise, its future as a new frontier in the treatment for cardiovascular disease will rest heavily on how we move forward in the next few years. Its success will heavily depend upon conducting carefully controlled, randomized double-blind clinical trials with appropriate endpoints, in the right patients. Choice of cell type, and mode of cell delivery, will also have to be considered, and may have to be matched to the patient. Irrespective of cell type, we can also be assured that cells offer both an opportunity for tissue repair and the potential for not yet understood outcomes. As with any frontier, there will be pitfalls and consequences to be considered that may surpass those of previous endeavors. But so too is the potential for previously unimagined success at treating the leading cause of death in the western world. In short, the promise for cardiovascular cell therapy is too great to be spoiled by ill-designed attempts that forget to account for both the natural propensities of cells and of the myocardium.

Cardiomyopathies↗
PubMed2003

Genesis of the monophasic action potential: role of interstitial resistance and boundary gradients.

The extracellular potential at the site of a mechanical deformation has been shown to resemble the underlying transmembrane action potential, providing a minimally invasive way to access membrane dynamics. The biophysical factors underlying the genesis of this signal, however, are still poorly understood. With the use of data from a recent experimental study in a murine heart, a three-dimensional anisotropic bidomain model of the mouse ventricular free wall was developed to study the currents and potentials resulting from the application of a point mechanical load on cardiac tissue. The applied pressure is assumed to open nonspecific pressure-sensitive channels depolarizing the membrane, leading to monophasic currents at the electrode edge that give rise to the monophasic action potential (MAP). The results show that the magnitude and the time course of the MAP are reproduced only for certain combinations of local or global intracellular and interstitial resistances that form a resting tissue length constant that, if applied over the entire domain, is smaller than that required to match the wave speed. The results suggest that the application of pressure not only causes local depolarization but also changes local tissue properties, both of which appear to play a critical role in the genesis of the MAP.

Action Potentials↗
PubMed2003

Comparison of intracardiac cell transplantation: autologous skeletal myoblasts versus bone marrow cells.

BACKGROUND: Multiple cell types are being proposed for cardiac repair, but side-by-side comparisons are lacking. We tested the hypothesis that intracardiac transplantation of autologous bone marrow- or skeletal muscle-derived progenitor cells improve regional heart function to a similar degree. METHODS AND RESULTS: Thirty-nine New Zealand White rabbits underwent cryoinjury of the left ventricle and simultaneous hind limb bone marrow aspiration or soleus muscle biopsy. Both muscle and bone marrow cells were expanded in vitro. After 2 weeks, 10(8) skeletal muscle (SM group) or bone marrow-derived progenitor cells (BM group) were injected into the cryoinjured region (SM: n=12; BM: n=8). Medium alone was injected into the remaining animals (Control: n=16). Regional systolic function was measured using micromanometry and sonomicrometry at baseline, before, and 4 weeks after cell injection. Cell treatment resulted in a similar degree of improvement in a derivative of stroke work in the SM and BM groups (P=0.0026 and P=0.0085 versus Control, respectively). No significant difference was seen between BM and SM groups (P=0.9). On histology, engrafted cells were found in all of the cell treated animals. Injected myoblasts formed myotubes or muscle cells throughout the scar that expressed slow and fast myosin heavy chain. A subset of bone marrow cells differentiated toward a myogenic phenotype, as indicated by expression of desmin and alpha-sarcomeric actin in the engrafted areas. CONCLUSIONS: Transplantation and myogenic differentiation of bone marrow-derived progenitor cells increased regional systolic heart function after myocardial injury to a similar degree as skeletal myoblasts.

Animals↗
PubMed2003

Aging, progenitor cell exhaustion, and atherosclerosis.

BACKGROUND: Atherosclerosis is largely attributed to chronic vascular injury, as occurs with excess cholesterol; however, the effect of concomitant vascular aging remains unexplained. We hypothesize that the effect of time in atherosclerosis progression is related to obsolescence of endogenous progenitor cells that normally repair and rejuvenate the arteries. METHODS AND RESULTS: Here we show that chronic treatment with bone marrow-derived progenitor cells from young nonatherosclerotic ApoE-/- mice prevents atherosclerosis progression in ApoE-/- recipients despite persistent hypercholesterolemia. In contrast, treatment with bone marrow cells from older ApoE-/- mice with atherosclerosis is much less effective. Cells with vascular progenitor potential are decreased in the bone marrow of aging ApoE-/- mice, but cells injected from donor mice engraft on recipient arteries in areas at risk for atherosclerotic injury. CONCLUSIONS: Our data indicate that progressive progenitor cell deficits may contribute to the development of atherosclerosis.

Age Factors↗