Search

Adult progenitor cell transplantation has been proposed for the treatment of heart failure, but the mechanisms effecting functional improvements remain unknown. The aim of this study was to test the hypothesis that, in failing hearts treated with cell transplantation, the mechanical properties and excitation-contraction coupling of recipient cardiomyocytes are altered. Adult rats underwent coronary artery ligation, leading to myocardial infarction and chronic heart failure. After 3 wk, they received intramyocardial injections of either [10.sup.7] green fluorescence protein (GFP)-positive bone marrow mononuclear cells or 5 x [10.sup.6] GFP-positive skeletal myoblasts. Four weeks after injection, both cell types increased ejection fraction and reduced cardiomyocyte size. The contractility of isolated GFP-negative cardiomyocytes was monitored by sarcomere shortening assessment, [Ca.sup.2+] handling by indo-1 and fluo-4 fluorescence, and electrophysiology by patch-clamping techniques. Injection of either bone marrow cells or skeletal myoblasts normalized the impaired contractile performance and the prolonged time to peak of the [Ca.sup.2+] transient observed in failing cardiomyocytes. The smaller and slower L-type [Ca.sup.2+] current observed in heart failure normalized after skeletal myoblast, but not bone marrow cell, transplantation. Measurement of [Ca.sup.2+] sparks suggested a normalization of sarcoplasmic reticulum [Ca.sup.2+] leak after skeletal myoblast transplantation. The increased [Ca.sup.2+] wave frequency observed in failing myocytes was reduced by either bone marrow cells or skeletal myoblasts. In conclusion, the morphology, contractile performance, and excitation-contraction coupling of individual recipient cardiomyocytes are altered in failing hearts treated with adult progenitor cell transplantation. heart failure; cell therapy; excitation-contraction coupling; cell electrophysiology; paracrine mechanims

Adipose tissue-derived stromal cells (ADSC) potentially differentiate into various cell types similar to bone marrow-derived mesenchymal stromal cells (BMSC). Unlike BMSC, ADSC can be harvested easily and repeatedly. However, the advantages of ADSC for cell transplantation in liver disease remain unclear. To investigate this, we developed a novel culture system for ADSC, as well as effective methods for transplantation of ADSC into mice liver. ADSC were isolated from subcutaneous adipose tissues of male C57BL6/J mice and cultured on plastic dishes with or without basic fibroblast growth factor (bFGF). In the in vivo study, ADSC isolated from green fluorescent protein-transgenic mice were transplanted into carbon tetrachloride-injured C57BL6/J mice liver. bFGF-treated ADSC expressed several liver-specific marker genes and demonstrated liver-related functions such as albumin secretion, glycogen synthesis, urea production, and low-density lipoprotein uptake. Importantly, pretreatment of ADSC with bFGF for 1 wk enhanced the repopulation rate of ADSC in mice liver, attenuated liver fibrosis, and restored normal serum alanine aminotransferase and albumin levels. The results indicate that basic FGF facilitates transdifferentiation of ADSC into hepatic lineage cells in vitro and that transplantation of bFGF-pretreated ADSC reduced hepatic fibrosis in mice. ADSC are a potentially valuable source of cells for transplantation therapy. hepatic lineage cells; basic FGF; cell transplantation; transdifferentiation; [alpha]-smooth muscle actin

One of the fundamental principles underlying tissue engineering approaches is that newly formed tissue must maintain sufficient vascularization to support its growth. Efforts to induce vascular growth into tissue-engineered scaffolds have recently been dedicated to developing novel strategies to deliver specific biological factors that direct the recruitment of endothelial cell (EC) progenitors and their differentiation. The challenge, however, lies in orchestration of the cells, appropriate biological factors, and optimal factor doses. This study reports an approach as a step forward to resolving this dilemma by combining an ex vivo gene transfer strategy and EC transplantation. The utility of this approach was evaluated by using 3D poly(lactide-co-glycolide) (PLAGA) sintered microsphere scaffolds for bone tissue engineering applications. Our goal was achieved by isolation and transfection of adipose-derived stromal cells (ADSCs) with adenovirus encoding the cDNA of VEGF. We demonstrated that the combination of VEGF releasing ADSCs and ECs results in marked vascular growth within PLAGA scaffolds. We thereby delineate the potential of ADSCs to promote vascular growth into biomaterials. biomaterials | tissue engineering | VEGF | adipose derived stem cells | sintered microsphere matrix

Transplantation of healthy cells to repair organ damage or replace deficient functions constitutes a major goal of cell therapy. However, the mechanisms by which transplanted cells engraft, proliferate, and function remain unknown. To investigate whether host liver sinusoidal endothelium could be replaced with transplanted liver sinusoidal endothelial cells, we developed an animal model of tissue replacement that utilized a genetic system to identify transplanted cells and induced host-cell perturbations to confer a proliferative advantage to transplanted cells. Under these experimental conditions, transplanted cells engrafted efficiently and proliferated to replace substantial portions of the liver endothelium. Tissue studies demonstrated that transplanted cells became integral to the liver structure and reacquired characteristic endothelial morphology. Characterization of transplanted endothelial cells by membrane markers and studies of cellular function, including synthesis and release of coagulation factor VIII, demonstrated that transplanted cells were functionally intact. Further analysis showed that repopulation of the livers of mice that model hemophilia A with healthy endothelial cells restored plasma factor VIII activity and corrected their bleeding phenotype. Our studies therefore suggest that transplantation of healthy endothelial cells should be considered for cell therapy of relevant disorders and that endothelial reconstitution with transplanted cells may offer an excellent paradigm for defining organ-specific pathophysiological mechanisms., Introduction A major requirement of cell therapy concerns reconstitution of specific cell compartments. Recently, several studies established the possibility of replacing parenchymal liver cells with transplanted hepatic or extrahepatic donor-derived [...]

The Reinfusion of Enriched Progenitor Cells and Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI) trial was conducted to determine whether intracoronary infusion of enriched bone marrow (BMC) is associated with improved global left ventricular function in patients with myocardial infarction treated with state-of-the-art methods. Results show that after acute myocardial infarction, the intracoronary administration of BMC enhances recovery of left ventricular contractile function.

A randomized, controlled trial, known as the Autologous Stem-Cell Transplantation in Acute Myocardial Infarction (ASTAMI) study, was conducted to investigate whether intracoronary injection of autologous mononuclear bone marrow (BMC) results in a clinically important improvement in left ventricular function as measured by the left ventricular ejection factor (LVEF). Results showed no effects of intracoronary injection of autologous mononuclear BMC on global left ventricular function.