Background— Ex vivo expansion of resident cardiac stem cells, followed by delivery to the heart, may favor regeneration and functional improvement. Methods and Results— Percutaneous endomyocardial biopsy specimens grown in primary culture developed multicellular clusters known as cardiospheres, which were plated to yield cardiosphere-derived cells (CDCs). CDCs from human biopsy specimens and from comparable porcine samples were examined in vitro for biophysical and cytochemical evidence of cardiogenic differentiation. In addition, human CDCs were injected into the border zone of acute myocardial infarcts in immunodeficient mice. Biopsy specimens from 69 of 70 patients yielded cardiosphere-forming cells. Cardiospheres and CDCs expressed antigenic characteristics of stem cells at each stage of processing, as well as proteins vital for cardiac contractile and electrical function. Human and porcine CDCs cocultured with neonatal rat ventricular myocytes exhibited biophysical signatures characteristic of myocyt...

Regenerative Potential of Cardiosphere-Derived Cells Expanded From Percutaneous Endomyocardial Biopsy Specimens

Multipotent mesenchymal stromal cells (MSCs) represent a rare heterogeneous subset of pluripotent stromal cells that can be isolated from many different adult tissues that exhibit the potential to give rise to cells of diverse lineages. Numerous studies have reported beneficial effects of MSCs in tissue repair and regeneration. After culture expansion and in vivo administration, MSCs home to and engraft to injured tissues and modulate the inflammatory response through synergistic downregulation of proinflammatory cytokines and upregulation of both prosurvival and antiinflammatory factors. In addition, MSCs possess remarkable immunosuppressive properties, suppressing T-cell, NK cell functions, and also modulating dentritic cell activities. Tremendous progress has been made in preclinical studies using MSCs, including the ability to use allogeneic cells, which has driven the application of MSCs toward the clinical setting. This review highlights our current understanding into the biology of MSCs with particular emphasis on the cardiovascular and renal applications, and provides a brief update on the clinical status of MSC-based therapy.

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Mesenchymal Stromal Cells: Current Understanding and Clinical Status†

Bone-marrow-derived EPCs (endothelial progenitor cells) play an integral role in the regulation and protection of the endothelium, as well as new vessel formation. Peripheral circulating EPC number and function are robust biomarkers of vascular risk for a multitude of diseases, particularly CVD (cardiovascular disease). Importantly, using EPCs as a biomarker is independent of both traditional and non-traditional risk factors (e.g. hypertension, hypercholesterolaemia and C-reactive protein), with infused ex vivo-expanded EPCs showing potential for improved endothelial function and either reducing the risk of events or enhancing recovery from ischaemia. However, as the number of existing cardiovascular risk factors is variable between patients, simple EPC counts do not adequately describe vascular disease risk in all clinical conditions and, as such, the risk of CVD remains. It is likely that this limitation is attributable to variation in the definition of EPCs, as well as a difference in the interaction between EPCs and other cells involved in vascular control such as pericytes, smooth muscle cells and macrophages. For EPCs to be used regularly in clinical practice, agreement on definitions of EPC subtypes is needed, and recognition that function of EPCs (rather than number) may be a better marker of vascular risk in certain CVD risk states. The present review focuses on the identification of measures to improve individual risk stratification and, further, to potentially individualize patient care to address specific EPC functional abnormalities. Herein, we describe that future therapeutic use of EPCs will probably rely on a combination of strategies, including optimization of the function of adjunct cell types to prime tissues for the effect of EPCs.

Endothelial progenitor cells: novel biomarker and promising cell therapy for cardiovascular disease.

Clinical trials with adult stem/progenitor cells for tissue repair: let's not overlook some essential precautions.

Background: One of the reasons for bone remodeling leading to an insufficient creeping substitution after osteonecrosis in the femoral head may be the small number of progenitor cells in the proximal femur and the trochanteric region. Because of this lack of progenitor cells, treatment modalities should stimulate and guide bone remodeling to sufficient creeping substitution to preserve the integrity of the femoral head. Core decompression with bone graft is used frequently in the treatment of osteonecrosis of the femoral head. In the current series, grafting was done with autologous bone marrow obtained from the iliac crest of patients operated on for early stages of osteonecrosis of the hip before collapse with the hypothesis that before stage of subchondral collapse, increasing the number of progenitor cells in the proximal femur will stimulate bone remodeling and creeping substitution and thereby improve functional outcome. Materials and Methods: Between 1990 and 2000, 342 patients (534 hips) with avascular osteonecrosis at early stages (Stages I and II) were treated with core decompression and autologous bone marrow grafting obtained from the iliac crest of patients operated on for osteonecrosis of the hip. The percentage of hips affected by osteonecrosis in this series of 534 hips was 19% in patients taking corticosteroids, 28% in patients with excessive alcohol intake, and 31% in patients with sickle cell disease. The mean age of the patients at the time of decompression and autologous bone marrow grafting was 39 years (range: 16-61 years). The aspirated marrow was reduced in volume by concentration and injected into the femoral head after core decompression with a small trocar. To measure the number of progenitor cells transplanted, the fibroblast colony forming unit was used as an indicator of the stroma cell activity. Results: Patients were followed up from 8 to 18 years. The outcome was determined by the changes in the Harris hip score, progression in radiographic stages, change in volume determined by digitizing area of the necrosis on the different cuts obtained on MRI, and by the need for hip replacement. Total hip replacement was necessary in 94 hips (evolution to collapse) among the 534 hips operated before collapse (Stages I and II). Sixty-nine hips with stage I osteonecrosis of the femoral head at the time of surgery demonstrated total resolution of osteonecrosis based on preoperative and postoperative MRI studies; these hips did not show any changes on plain radiographs. Before treatment, these 69 osteonecrosis had only a marginal band like pattern as abnormal signal and a volume less than 20 cubic centimeters. The intralesional area had kept a normal signal as regards the signal of the femoral head outside the osteonecrosis area. For the 371 other hips without collapse at the most recent follow up (average 12 years), the mean preoperative volume of the osteonecrosis was 26 cm 3 (minimum 12, maximum 30 cm 3 ). The mean volume of the abnormal signal measured on MRI at the most recent follow up (mean 12 years) was 12 cm 3 . The abnormal signal persisting as a sequelae was seen on T1 images as an intralesional area of low intensity signal with a disappearance of the marginal band like pattern. Conclusion: According to our experience, best indication for the procedure is symptomatic hips with osteonecrosis without collapse. In some patients who had Steinberg stage III osteonecrosis (subchondral lucency, no collapse) successful outcomes (no further surgery) has been obtained between 5 to 10 years. Therefore in selected patients, even more advanced disease can be considered for core decompression. Patients who had the greater number of progenitor cells transplanted in their hips had better outcomes.

Cell therapy of hip osteonecrosis with autologous bone marrow grafting.

Background— Cell-based therapies for treatment of ischemic heart disease are currently under investigation. We previously reported the results of a phase I trial of transendocardial injection of autologous bone marrow mononuclear (ABMM) cells in patients with end-stage ischemic heart disease. The current report focuses on postmortem cardiac findings from one of the treated patients, who died 11 months after cell therapy. Methods and Results— Anatomicopathologic, morphometric, and immunocytochemical findings from the anterolateral ventricular wall (with cell therapy) were compared with findings from the interventricular septum (normal perfusion and no cell therapy) and from the inferoposterior ventricular wall (extensive scar tissue and no cell therapy). No signs of adverse events were found in the cell-injected areas. Capillary density was significantly higher (P<0.001) in the anterolateral wall than in the previously infarcted tissue in the posterior wall. The prominent vasculature of the anterolateral w...

http://www.kumc.edu/Documents/msctc/Circulation-2005-Dohmann-521-6.pdf

Transendocardial Autologous Bone Marrow Mononuclear Cell Injection in Ischemic Heart Failure Postmortem Anatomicopathologic and Immunohistochemical Findings

Rodrigo V. Castello-Branco

Papers

Transendocardial Autologous Bone Marrow Mononuclear Cell Injection in Ischemic Heart Failure Postmortem Anatomicopathologic and Immunohistochemical Findings