Sustained Persistence of Transplanted Proangiogenic Cells Contributes to Neovascularization and Cardiac Function After Ischemia

Abstract

Abstract-Circulating blood-derived vasculogenic cells improve neovascularization of ischemic tissue by a broad repertoire of potential therapeutic actions. Whereas initial studies documented that the cells incorporate and differentiate to cardiovascular cells, other studies suggested that short-time paracrine mechanisms mediate the beneficial effects. The question remains to what extent a physical incorporation is contributing to the beneficial effects of cell therapy. By using the inducible suicide gene thymidine kinase to deplete transplanted cells, we determined the contribution of physical incorporation in 3 animal models. After acute myocardial infarction, depletion of cells 14 days after infusion resulted in a reduction of capillary density and a substantial deterioration of heart function. Likewise, neovascularization of Matrigel plugs and ischemic limbs was significantly suppressed when infused cells were depleted 7 days after infusion. Key Words: progenitor cells Ⅲ neovascularization Ⅲ cell therapy C ell therapy is a promising option for treating ischemic diseases. Adult stem and progenitor cells from various sources have experimentally been shown to augment the functional recovery after ischemia. Clinical trials confirmed that autologous cell therapy using bone marrow-derived or circulating blood-derived progenitor cells is safe and provides beneficial effects 1-3 (see also recent metaanalysis 4 ). Endothelial progenitor cells (EPCs) were initially isolated from bone marrow or peripheral blood and were characterized by the expression of the hematopoietic stem cell marker CD34 or CD133 and endothelial markers such as vascular endothelial growth factor receptor 2 (KDR). 5,6 Isolated CD34 ϩ cells differentiate to endothelial cells in vitro and incorporate into newly formed vessels during angiogenesis in vivo. 5 These pioneering studies suggested that bone marrow-derived cells can participate in vascular repair. Indeed, a single hematopoietic stem cell was shown to give rise to both blood cells and vascular endothelium. [7][8][9] The contribution of circulating cells to the endothelium was further supported by sexmismatched heart transplantation in humans. 10,11 Other investigators used culture assays to enrich for EPC-yielding cells, which coexpress endothelial and myeloid marker ("early EPCs," proangiogenic cells), or to show a more mature endothelial cell phenotype on further culture and expansion ("late or outgrowing EPCs"). 12,13 Although the origin and the phenotype of the cultured EPCs is not entirely clear and may vary depending on the defined specific culture conditions, 14 the therapeutic potential and improved neovascularization mediated by the cultured cells has been documented extensively in ischemic models. 12,15,16 Progenitor cell-mediated improved neovascularization of ischemic tissue might be attributable to various therapeutic actions including a physical incorporation of the infused cells in the endothelium leading to the formation of new capillaries. 16 -18 Transplanted or infused hema...

Regenerating new heart with stem cells

“…However, mononuclear bone marrow cells should not be confused with c-kit-positive HSCs that constitute a minute fraction of the mononuclear bone marrow cell pool (105). Experimentally, remarkable levels of myocardial regeneration after infarction have been obtained with c-kit-positive HSCs (71,72,75,85) but not with mononuclear bone marrow cells (106). At present, it is unknown whether CSCs and HSCs are similarly effective in reconstituting the necrotic and scarred tissue, or whether limitations exist in CSC growth and HSC transdifferentiation, resulting in inadequate restoration of the damaged myocardium.…”

A Randomized Comparative Study on the Efficacy of Intracoronary Infusion of Autologous Bone Marrow Mononuclear Cells and Mesenchymal Stem Cells in Patients With Dilated Cardiomyopathy

“…These findings are similar to a number of other studies that showed that the clinical benefits of cell therapy were sustained with BMSC. 16,27,32) However, a significant decrease in LVEF was observed in the BMMC group in comparison with the values at the 3-month follow-up, in accordance with the BOOST trial, in which patients received BMMC or conventional therapy and which demonstrated that cardiac performance improved significantly in the cell therapy group at a 6-month follow-up, 6) whereas the benefit was not observed at 18 months following administration. 33) The temporal changes in improvement in LVEF and NYHA class suggested that BMMC transplantation only accelerates cardiac function recovery and that most of the beneficial effects are observed soon after stem cell delivery.…”

“…6,25) Based on this evidence, larger trials have confirmed that intracoronary injection of autologous BMC is safe and potentially effective. 26) The beneficial effects of cell therapy in the setting of ischemic heart disease are not fully understood, and proposed mechanisms of action have included cardiomyocyte regeneration, 3,5,22) angiogenesis, [3][4][5]16,21,22,25) and inhibition of myocardial apoptosis and ventricular remodeling through paracrine factors of the infused cells. 3,14,21) The capacity of BMC to regenerate myocytes has been a matter of intense debate to date.…”

“…3,4) Intracoronary administration of autologous bone marrow stem cells (BMC) has proved to be safe and has shown significant improvement of cardiac function in the treatment of post-infarct and chronic ischemic models in both preclinical and clinical settings. [5][6][7][8] Because severely reduced coronary flow reserve and impaired microvascular function have been observed in patients with DCM, 9,10) several clinical studies have applied cell therapy to these patients, 4,[11][12][13][14] despite much controversy concerning the underlying mechanisms [3][4][5][14][15][16] and conflicting results from the procedure. 12,13) Most of these studies performed intracoronary infusion using either bone marrow mononuclear cells (BMMC), which are non-selected bone marrow stem cells, or bone marrow mesenchymal stem cells (BMSC).…”

Thérapies cellulaires pro-angiogéniques dans le traitement des pathologies ischémiques

“…Ainsi, dans un modèle d'ischémie des membres inférieurs et du myocarde chez la souris nude greffée avec des cellules humaines pro-angiogéniques transduites avec un gène « suicide » (séquence du gène TK, thymidine kinase, du virus herpes simplex de type 2), l'induction de la mort des cellules progénitrices par le ganciclovir 14 jours après leur injection annule le bénéfice thérapeutique sur la fonction cardiaque. Cela révèle ainsi que l'incorporation physique et la persistance des cellules contribuent à l'effet de ces dernières sur la vascularisation et la fonction cardiaque [25] et conforte l'hypothèse d'une complémentarité des mécanismes paracrines et intrinsèques.…”