Biomedical subjects

Michael A Laflamme

Publications and source records attributed to Michael A Laflamme.

6 recordsLinked to original sources

PubMed2006

Confirmation of Chagas' cardiomyopathy following heart transplantation.

We report a case of Chagas' cardiomyopathy confirmed in a patient after heart transplantation. The patient initially presented with symptoms of congestive heart failure and was found to have positive serology for prior Trypanosoma cruzi infection. Despite optimal medical management, the patient had deterioration of his cardiac function and he underwent heart transplantation. Pathology examination of the explanted heart confirmed Chagas' cardiomyopathy. The cardiac sequelae of Chagas' disease include arrhythmias, aneurysm, thromboembolism, cardiomyopathy, and sudden death. We review the epidemiology, cardiac pathology, and evaluation of patients with Chagas' cardiac disease. We discuss the clinical features of Chagas' cardiomyopathy and available treatments including cardiac transplantation.

Animals↗

PubMed2005

Extracardiac progenitor cells repopulate most major cell types in the transplanted human heart.

BACKGROUND: Extracardiac progenitor cells are capable of repopulating cardiomyocytes at very low levels in the human heart after injury. Here, we explored the extent of endothelial, smooth muscle, and Schwann cell chimerism in patients with sex-mismatched (female-to-male) heart transplants. METHODS AND RESULTS: Autopsy specimens from 5 patients and endomyocardial biopsies from 7 patients were used for this study. Endothelial, vascular smooth muscle, and Schwann cells were stained with antibodies against CD31 or Ulex europaeus lectin, smooth muscle alpha-actin, and S-100, respectively, and the Y chromosome was identified with in situ hybridization. Biopsy specimens from 1, 4, 6, and 12 months and 5 and 10 years after heart transplantation were evaluated. Y-positive cells were counted by conventional bright-field microscopy and confirmed by confocal microscopy. Endothelial cells showed the highest degree of chimerism, averaging 24.3+/-8.2% from extracardiac sources. Schwann cells showed the next highest chimerism, averaging 11.2+/-2.1%; vascular smooth muscle cells averaged 3.4+/-1.8%. All 3 cell types showed substantially higher chimerism than we previously observed for cardiomyocytes (0.04+/-0.05%). Endothelial chimerism was much higher in the microcirculation than in larger vessels. Analysis of serial endomyocardial biopsies revealed that high levels of endothelial chimerism occurred as early as 1 month after transplantation (22+/-6.6%) with no significant increases even up to 10 years after cardiac transplantation. CONCLUSIONS: Extracardiac progenitor cells are capable of repopulating most major cell types in the heart, but they do so with varying frequency. The signals for endothelial progenitor recruitment occur early and could relate to injury during allograft harvest or transplantation. The high degree of endothelial chimerism may have immune implications such as for myocardial rejection or graft vasculopathy.

Adult↗

PubMed2005

Proliferation of cardiomyocytes derived from human embryonic stem cells is mediated via the IGF/PI 3-kinase/Akt signaling pathway.

Cardiomyocytes from common experimental animals rapidly exit the cell cycle upon isolation, impeding studies of basic cell biology and applications such as myocardial repair. Here we examined proliferation of cardiomyocytes derived from human and mouse embryonic stem (ES) cells. While mouse ES cell-derived cardiomyocytes showed little proliferation, human cardiomyocytes were highly proliferative under serum-free conditions (15-25% BrdU+/sarcomeric actin+). The cells exhibited only a small serum dose-response, and proliferation gradually slowed with increasing differentiation of the cells. Neither cell density nor different matrix attachment factors affected cardiomyocyte proliferation. Blockade of phosphatidylinositol 3-kinase (PI 3-kinase) and Akt significantly reduced cardiomyocyte proliferation, whereas MEK inhibition had no effect. Antibody blocking of the insulin-like growth factor-1 (IGF-1) receptor significantly inhibited cardiomyocyte proliferation, while addition of IGF-1 or IGF-2 stimulated cardiomyocyte proliferation in a dose-dependent manner. Thus, cardiomyocytes derived from human ES cells proliferate extensively in vitro, and their proliferation appears to be mediated primarily via the PI 3-kinase/Akt signaling pathway, using the IGF-1 receptor as one upstream activator. This system should permit identification of regulatory pathways for human cardiomyocyte proliferation and may facilitate expansion of cardiomyocytes from human ES cells for therapeutic purposes.

Animals↗

PubMed2005

Formation of human myocardium in the rat heart from human embryonic stem cells.

Human embryonic stem cells (hESCs) offer the opportunity to replenish cells lost in the postinfarct heart. We explored whether human myocardium could be generated in rat hearts by injecting differentiated cardiac-enriched hESC progeny into the left ventricular wall of athymic rats. Although initial grafts were predominantly epithelial, noncardiac elements were lost over time, and grafts consisted predominantly of cardiomyocytes by 4 weeks. No teratomatous elements were observed. Engrafted cardiomyocytes were glycogen-rich and expressed expected cardiac markers including beta-myosin heavy chain, myosin light chain 2v, and atrial natriuretic factor. Heat-shock treatment improved graft size approximately threefold. The cardiac implants exhibited substantial angiogenesis, both recipient and graft derived. Importantly, there was greater proliferation in human cardiomyocytes than previously seen in rodent-derived cardiomyocytes: 14.4% of graft cardiomyocytes expressed the proliferation marker Ki-67, and 2.7% incorporated the thymidine analog BrdU 4 weeks after transplantation. This proliferation was associated with a sevenfold increase in graft size over the 4-week interval. Thus, hESCs can form human myocardium in the rat heart, permitting studies of human myocardial development and physiology and supporting the feasibility of their use in myocardial repair.

Animals↗

PubMed2005

Regenerating the heart.

Cell-based cardiac repair offers the promise of rebuilding the injured heart from its component parts. Work began with committed cells such as skeletal myoblasts, but recently the field has expanded to explore an array of cell types, including bone marrow cells, endothelial progenitors, mesenchymal stem cells, resident cardiac stem cells, and both mouse and human embryonic stem cells. A related strategy for cardiac repair involves cell mobilization with factors such as cytokines. Translation of cell-based approaches to the clinic has progressed rapidly, and clinical trials using autologous skeletal myoblasts and bone marrow cells are under way. Many challenges remain before the vision of healing an infarct by muscle regeneration can be realized. Future research is likely to focus on improving our ability to guide the differentiation of stem cells, control their survival and proliferation, identify factors that mediate their homing and modulate the heart's innate inflammatory and fibrotic responses.

Animals↗

PubMed2002

Evidence for cardiomyocyte repopulation by extracardiac progenitors in transplanted human hearts.

Human myocardium has long been considered to have essentially no intrinsic regenerative capacity. Recent studies in rodent models, however, have suggested the presence of an extracardiac stem cell population, perhaps in bone marrow, that is capable of some reconstitution of cardiomyocytes after injury. To determine whether similar mechanisms exist in the human heart, we evaluated human female allograft hearts transplanted into male patients. The presence of Y chromosomes in cardiomyocytes would indicate these cells arose from the recipient, rather than the donor heart. We identified 5 male patients who had retained a female heart at least 9 months before death and necropsy. Remarkably, in each case, the transplanted heart contained a minute but readily detectable fraction of Y chromosome-positive cardiomyocytes. The mean percentage of cardiomyocytes arising from the host was estimated to be 0.04% with a median of 0.016%. Most Y-positive cardiomyocytes were associated with regions of acute rejection, suggesting such chimerism involves an injury event. Furthermore, the sole patient whose immediate cause of death was allograft rejection showed a much higher percentage of host-derived cardiomyocytes, up to 29% in local, 1-mm(2) "hot spots." Thus, adult humans have extracardiac progenitor cells capable of migrating to and repopulating damaged myocardium, but this process occurs at very low levels.

Cell Differentiation↗