Showing papers by "Annarosa Leri published in 2008"

Aging and Disease as Modifiers of Efficacy of Cell Therapy

Abstract: Cell therapy is a promising option for treating ischemic diseases and heart failure. Adult stem and progenitor cells from various sources have experimentally been shown to augment the functional recovery after ischemia, and clinical trials have confirmed that autologous cell therapy using bone marrow—derived or circulating blood-derived progenitor cells is safe and provides beneficial effects. However, aging and risk factors for coronary artery disease affect the functional activity of the endogenous stem/progenitor cell pools, thereby at least partially limiting the therapeutic potential of the applied cells. In addition, age and disease affect the tissue environment, in which the cells are infused or injected. The present review article will summarize current evidence for cell impairment during aging and disease but also discuss novel approaches how to reverse the dysfunction of cells or to refresh the target tissue. Pretreatment of cells or the target tissue by small molecules, polymers, growth factors, or a combination thereof may provide useful approaches for enhancement of cell therapy for cardiovascular diseases. (Circ Res. 2008;102:1319-1330.)

Local Activation or Implantation of Cardiac Progenitor Cells Rescues Scarred Infarcted Myocardium Improving Cardiac Function

Abstract: Ischemic heart disease is characterized chronically by a healed infarct, foci of myocardial scarring, cavitary dilation, and impaired ventricular performance. These alterations can only be reversed by replacement of scarred tissue with functionally competent myocardium. We tested whether cardiac progenitor cells (CPCs) implanted in proximity of healed infarcts or resident CPCs stimulated locally by hepatocyte growth factor and insulin-like growth factor-1 invade the scarred myocardium and generate myocytes and coronary vessels improving the hemodynamics of the infarcted heart. Hepatocyte growth factor is a powerful chemoattractant of CPCs, and insulin-like growth factor-1 promotes their proliferation and survival. Injection of CPCs or growth factors led to the replacement of approximately 42% of the scar with newly formed myocardium, attenuated ventricular dilation and prevented the chronic decline in function of the infarcted heart. Cardiac repair was mediated by the ability of CPCs to synthesize matrix metalloproteinases that degraded collagen proteins, forming tunnels within the fibrotic tissue during their migration across the scarred myocardium. New myocytes had a 2n karyotype and possessed 2 sex chromosomes, excluding cell fusion. Clinically, CPCs represent an ideal candidate cell for cardiac repair in patients with chronic heart failure. CPCs may be isolated from myocardial biopsies and, following their expansion in vitro, administered back to the same patients avoiding the adverse effects associated with the use of nonautologous cells. Alternatively, growth factors may be delivered locally to stimulate resident CPCs and promote myocardial regeneration. These forms of treatments could be repeated over time to reduce progressively tissue scarring and expand the working myocardium.

Notch1 regulates the fate of cardiac progenitor cells

Abstract: The Notch receptor mediates cell fate decision in multiple organs. In the current work we tested the hypothesis that Nkx2.5 is a target gene of Notch1 and raised the possibility that Notch1 regulates myocyte commitment in the adult heart. Cardiac progenitor cells (CPCs) in the niches express Notch1 receptor, and the supporting cells exhibit the Notch ligand Jagged1. The nuclear translocation of Notch1 intracellular domain (N1ICD) up-regulates Nkx2.5 in CPCs and promotes the formation of cycling myocytes in vitro. N1ICD and RBP-Jk form a protein complex, which in turn binds to the Nkx2.5 promoter initiating transcription and myocyte differentiation. In contrast, transcription factors of vascular cells are down-regulated by Jagged1 activation of the Notch1 pathway. Importantly, inhibition of Notch1 in infarcted mice impairs the commitment of resident CPCs to the myocyte lineage opposing cardiomyogenesis. These observations indicate that Notch1 favors the early specification of CPCs to the myocyte phenotype but maintains the newly formed cells in a highly proliferative state. Dividing Nkx2.5-positive myocytes correspond to transit amplifying cells, which condition the replicative capacity of the heart. In conclusion, Notch1 may have critical implications in the control of heart homeostasis and its adaptation to pathologic states.

Activation of Cardiac Progenitor Cells Reverses the Failing Heart Senescent Phenotype and Prolongs Lifespan

Abstract: Heart failure is the leading cause of death in the elderly, but whether this is the result of a primary aging myopathy dictated by depletion of the cardiac progenitor cell (CPC) pool is unknown. Similarly, whether current lifespan reflects the ineluctable genetic clock or heart failure interferes with the genetically determined fate of the organ and organism is an important question. We have identified that chronological age leads to telomeric shortening in CPCs, which by necessity generate a differentiated progeny that rapidly acquires the senescent phenotype conditioning organ aging. CPC aging is mediated by attenuation of the insulin-like growth factor-1/insulin-like growth factor-1 receptor and hepatocyte growth factor/c-Met systems, which do not counteract any longer the CPC renin-angiotensin system, resulting in cellular senescence, growth arrest, and apoptosis. However, pulse-chase 5-bromodeoxyuridine-labeling assay revealed that the senescent heart contains functionally competent CPCs that have the properties of stem cells. This subset of telomerase-competent CPCs have long telomeres and, following activation, migrate to the regions of damage, where they generate a population of young cardiomyocytes, reversing partly the aging myopathy. The senescent heart phenotype and heart failure are corrected to some extent, leading to prolongation of maximum lifespan.

Formation of large coronary arteries by cardiac progenitor cells

Abstract: Coronary artery disease is the most common cause of cardiac failure in the Western world, and to date there is no alternative to bypass surgery for severe coronary atherosclerosis. We report that c-kit-positive cardiac progenitor cells (CPCs) activated with insulin-like growth factor 1 and hepatocyte growth factor before their injection in proximity of the site of occlusion of the left coronary artery in rats, engrafted within the host myocardium forming temporary niches. Subsequently, CPCs divided and differentiated into endothelial cells and smooth muscle cells and, to a lesser extent, into cardiomyocytes. The acquisition of vascular lineages appeared to be mediated by the up-regulation of hypoxia-inducible factor 1α, which promoted the synthesis and secretion of stromal-derived factor 1 from hypoxic coronary vessels. Stromal-derived factor 1 was critical in the conversion of CPCs to the vascular fate. CPCs formed conductive and intermediate-sized coronary arteries together with resistance arterioles and capillaries. The new vessels were connected with the primary coronary circulation, and this increase in vascularization more than doubled myocardial blood flow in the infarcted myocardium. This beneficial effect, together with myocardial regeneration attenuated postinfarction dilated myopathy, reduced infarct size and improved function. In conclusion, locally delivered activated CPCs generate de novo coronary vasculature and may be implemented clinically for restoration of blood supply to the ischemic myocardium.

IGF-I alleviates diabetes-induced RhoA activation, eNOS uncoupling, and myocardial dysfunction

Abstract: IGF-I rescues diabetic heart defects and oxidative stress, although the underlying mechanism of action remains poorly understood. This study was designed to delineate the beneficial effects of IGF-...

Myocardial induction of nucleostemin in response to postnatal growth and pathological challenge.

Abstract: Stem cell-specific proteins and regulatory pathways that determine self-renewal and differentiation have become of fundamental importance in understanding regenerative and reparative processes in the myocardium. One such regulatory protein, named nucleostemin, has been studied in the context of stem cells and several cancer cell lines, where expression is associated with proliferation and maintenance of a primitive cellular phenotype. We find nucleostemin is present in young myocardium and is also induced following cardiomyopathic injury. Nucleostemin expression in cardiomyocytes is induced by fibroblast growth factor-2 and accumulates in response to Pim-1 kinase activity. Cardiac stem cells also express nucleostemin that is diminished in response to commitment to a differentiated phenotype. Overexpression of nucleostemin in cultured cardiac stem cells increases proliferation while preserving telomere length, providing a mechanistic basis for potential actions of nucleostemin in promotion of cell survival and proliferation as seen in other cell types.

Compositions comprising hdac inhibitors and methods of their use in restoring stem cell function and preventing heart failure

Abstract: The invention provides compositions of histone deacetylase (HDAC) inhibitors and progenitor cells useful for treating heart failure in a subject. The invention also provides methods of restoring progenitor cell function to aged progenitor cells and methods for enhancing progenitor cell proliferation and/or differentiation using HDAC inhibitors.

The human heart: a self-renewing organ.

Abstract: The dogma that the heart is a static organ which contains an irreplaceable population of cardiomyocytes prevailed in the cardiovascular field for the last several decades. However, the recent identification of progenitor cells that give rise to differentiated myocytes has prompted a re-interpretation of cardiac biology. The heart cannot be viewed any longer as a postmitotic organ characterized by a predetermined number of myocytes that is defined at birth and is preserved throughout life. The myocardium constitutes a dynamic entity in which new young parenchymal cells are formed to substitute old damaged dying myocytes. The regenerative ability of the heart was initially documented with a classic morphometric approach and more recently with the demonstration that DNA synthesis, mitosis, and cytokinesis take place in the newly formed myocytes of the normal and pathologic heart. Importantly, replicating myocytes correspond to the differentiated progeny of cardiac stem cells. These findings point to the possibility of novel therapeutic strategies for the diseased heart.

Methods of reducing transplant rejection and cardiac allograft vasculopathy by implanting autologous stem cells

Abstract: The invention provides novel methods of reducing transplant rejection and cardiac allograft vasculopathy in humans by employing the implantation of autologous progenitor cells into the transplanted donor heart. The autologous progenitor cells can be vascular progenitor cells (VPCs) and/or myocyte progenitor cells (MPCs) isolated from the recipient's explanted heart. Alternatively, bone marrow progenitor cells (BMPCs) isolated from the recipient may also be used.

Compositions comprising vascular and myocyte progenitor cells and methods of their use

Abstract: The invention provides compositions of adult cardiac vascular progenitor cells (VPCs) and adult cardiac myocyte progenitor cells (MPCs) useful for the treatment of various cardiac conditions. The invention also encompasses methods of generating a biological bypass, repairing damaged myocardium, and treating or preventing hypertensive cardiomyopathy and heart failure with the compositions of the invention. Methods of isolating the cardiac progenitor cells are also disclosed.

Cardiac Stem Cells and Myocardial Regeneration

Abstract: Until recently, the accepted paradigm considered the adult mammalian heart a post-mitotic organ without intrinsic regenerative capacity where neither myocyte death nor new myocyte formation played any role in its homeostasis and could be safely ignored. We have recently identified in the adult mammalian myocardium a small cell population expressing surface antigens commonly associated with a variety of stem cells. These cells have the behaviour and potential of bonafide cardiac stem cells (CSCs): they are clonogenic, self-renewing and multipotent. Their presence has identified myocyte death and myocyte renewal as the two sides of the proverbial coin of cardiac homeostasis. Myocyte renewal depends on the differentiation of the CSCs into immature myocytes that divide two to four times before becoming terminally differentiated. Both in vivo and in vitro the progeny of a single CSC can generate the three major cell types of the myocardium: myocytes, smooth muscle and endothelial vascular cells. More interestingly, when directly injected or activated with growth factors in the post-ischaemic myocardium, these cells are able to reconstitute a functional ventricular wall. Thus, although in the adult heart most cardiac myocytes are permanently withdrawn from the cell cycle, the heart has an intrinsic regenerative potential and it is not a terminally differentiated organ.

Correction: Corrigendum: Pim-1 regulates cardiomyocyte survival downstream of Akt

Abstract: Nat. Med. 13, 1467–1475 (2007); published online 25 November 2007; corrected after print 13 February 2008. In the version of this article initially published, the meanings of the error bars in the figures and supplementary figures and the error values given in Supplementary Table 2 were not stated. They represent the standard error of the mean in all cases except Supplementary Figure 5, where they represent the standard deviation.