According to recent findings, pathological processes may deplete adult heart of stem cells. The scope of the present study was to assess proliferation, apoptosis and commitment of cardiac stem cells (CSCs) resident in normal (n=11) and pathological hearts with ischemic cardiomyopathy (n=20). Immunofluorescence and immunoblotting of CSCs isolated from normal and pathological hearts revealed higher expression of cardiac-specific markers in the latter. Proliferation of CSCs isolated from pathological hearts was 3.2±0.7-fold higher, while apoptosis induced by oxidative stress was 1.8±0.2-fold higher than in the normal cells. Asymmetric division, with unequal Notch distribution between daughter cells, occurred frequently in CSCs from ischemic hearts, while symmetric division was typical of normal cells. Gene expression was examined by stem cells specific PCR-based microarray. We confined our analysis to genes with at least 1.7-fold differential expression. Genes downregulated in pathological hearts belonged to the early stages of developmental process (snail1 homolog, jagged-1, ephrin b1), cell cycle control (mdm2, p15 and p16), neurogenesis, skeletal development, bone remodeling and cartilage development functional classes. Upregulated genes, among which OTF2, endothelin receptor, CD105 and MRG1, were involved in developmental maturation, mesenchymal cell differentiation, heart development and circulatory system processes. Major finding emerging from the analysis was the activation of the epithelial-mesenchymal transition and the upregulation of its inducer, TGFβ. The expression of genes related to TGFβ BMP-mediated signal transduction pathway was examined by PCR Array. The analysis confirmed the upregulation of genes as TGFβ-1 and -3, Nodal, ID1 and c-Myc, suggesting the activation of mesenchyme formation and CSCs differentiation towards cardiac cell lineages. In conclusion, CSCs in the normal and in the pathological heart differ in several respects and the differences reflect the activation of cardiac stem cells pool in the chronic pathological conditions. Given the apparent failure of intrinsic heart regeneration, further studies are warranted to optimize the strategies for CSCs application in regenerative medicine.

Adult human cardiac stem cells become readily committed in pathological conditions: phenotypic and genetic evidence.

DI MEGLIO, FRANCA;CASTALDO, CLOTILDE;NURZYNSKA, DARIA ANNA;MIRAGLIA, RITA;ROMANO, VERONICA;AMATRUDA, NUNZIA;MONTAGNANI, STEFANIA
2010

Abstract

According to recent findings, pathological processes may deplete adult heart of stem cells. The scope of the present study was to assess proliferation, apoptosis and commitment of cardiac stem cells (CSCs) resident in normal (n=11) and pathological hearts with ischemic cardiomyopathy (n=20). Immunofluorescence and immunoblotting of CSCs isolated from normal and pathological hearts revealed higher expression of cardiac-specific markers in the latter. Proliferation of CSCs isolated from pathological hearts was 3.2±0.7-fold higher, while apoptosis induced by oxidative stress was 1.8±0.2-fold higher than in the normal cells. Asymmetric division, with unequal Notch distribution between daughter cells, occurred frequently in CSCs from ischemic hearts, while symmetric division was typical of normal cells. Gene expression was examined by stem cells specific PCR-based microarray. We confined our analysis to genes with at least 1.7-fold differential expression. Genes downregulated in pathological hearts belonged to the early stages of developmental process (snail1 homolog, jagged-1, ephrin b1), cell cycle control (mdm2, p15 and p16), neurogenesis, skeletal development, bone remodeling and cartilage development functional classes. Upregulated genes, among which OTF2, endothelin receptor, CD105 and MRG1, were involved in developmental maturation, mesenchymal cell differentiation, heart development and circulatory system processes. Major finding emerging from the analysis was the activation of the epithelial-mesenchymal transition and the upregulation of its inducer, TGFβ. The expression of genes related to TGFβ BMP-mediated signal transduction pathway was examined by PCR Array. The analysis confirmed the upregulation of genes as TGFβ-1 and -3, Nodal, ID1 and c-Myc, suggesting the activation of mesenchyme formation and CSCs differentiation towards cardiac cell lineages. In conclusion, CSCs in the normal and in the pathological heart differ in several respects and the differences reflect the activation of cardiac stem cells pool in the chronic pathological conditions. Given the apparent failure of intrinsic heart regeneration, further studies are warranted to optimize the strategies for CSCs application in regenerative medicine.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/374469
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