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Preservation of myocardial structure is enhanced by pim-1 engineering of bone marrow cells.

ABSTRACT: Bone marrow-derived cells to treat myocardial injury improve cardiac function and support beneficial cardiac remodeling. However, survival of stem cells is limited due to low proliferation of transferred cells.To demonstrate long-term potential of c-kit(+) bone marrow stem cells (BMCs) enhanced with Pim-1 kinase to promote positive cardiac remodeling.Lentiviral modification of c-kit(+) BMCs to express Pim-1 (BMCeP) increases proliferation and expression of prosurvival proteins relative to BMCs expressing green fluorescent protein (BMCe). Intramyocardial delivery of BMCeP at time of infarction supports improvements in anterior wall dimensions and prevents left ventricle dilation compared with hearts treated with vehicle alone. Reduction of the akinetic left ventricular wall was observed in BMCeP-treated hearts at 4 and 12 weeks after infarction. Early recovery of cardiac function in BMCeP-injected hearts facilitated modest improvements in hemodynamic function up to 12 weeks after infarction between cell-treated groups. Persistence of BMCeP is improved relative to BMCe within the infarct together with increased recruitment of endogenous c-kit(+) cells. Delivery of BMC populations promotes cellular hypertrophy in the border and infarcted regions coupled with an upregulation of hypertrophic genes. Thus, BMCeP treatment yields improved structural remodeling of infarcted myocardium compared with control BMCs.Genetic modification of BMCs with Pim-1 may serve as a therapeutic approach to promote recovery of myocardial structure. Future approaches may take advantage of salutary BMC actions in conjunction with other stem cell types to increase efficacy of cellular therapy and improve myocardial performance in the injured myocardium.

SUBMITTER: Quijada P

PROVIDER: S-EPMC3398618 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Preservation of myocardial structure is enhanced by pim-1 engineering of bone marrow cells.

Quijada Pearl P Toko Haruhiro H Fischer Kimberlee M KM Bailey Brandi B Reilly Patrick P Hunt Kristin D KD Gude Natalie A NA Avitabile Daniele D Sussman Mark A MA

Circulation research 20120522 1

<h4>Rationale</h4>Bone marrow-derived cells to treat myocardial injury improve cardiac function and support beneficial cardiac remodeling. However, survival of stem cells is limited due to low proliferation of transferred cells.<h4>Objective</h4>To demonstrate long-term potential of c-kit(+) bone marrow stem cells (BMCs) enhanced with Pim-1 kinase to promote positive cardiac remodeling.<h4>Methods and results</h4>Lentiviral modification of c-kit(+) BMCs to express Pim-1 (BMCeP) increases prolife ...[more]

PMID: 22619278

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Project description:Inducing axial vascularisation of tissue engineering constructs is a well-established method to support tissue growth in large 3-dimensional tissues. Progenitor cell chemotaxis towards axially vascularized tissues has not been well characterized. In a prospective randomized controlled study including 32 male syngeneic Lewis rats we investigated the capability of the axially vascularized constructs to attract systemically injected bone marrow mononuclear cells (BMMNCs). The underlying mechanism for cell homing was investigated focusing on the role of hypoxia and the SDF1-CXCR4-7 axis. Sixteen animals were used as donors for BMMNCs. The other animals were subjected to implantation of a tissue engineering construct in the subcutaneous groin region. These constructs were axially vascularized either via an arteriovenous loop (AVL, n = 6) or via uninterrupted flow-through vessels (non-AVL, n = 10). BMMNCs were labelled with quantum dots (Qdot® 655) and injected 12 days after surgery either via intra-arterial or intravenous routes. 2 days after cell injection, the animals were sacrificed and examined using fluorescence microscopy. The Qdot® 655 signals were detected exclusively in the liver, spleen, AVL constructs and to a minimal extent in the non-AVL constructs. A significant difference could be detected between the number of labelled cells in the AVL and non-AVL constructs with more cells detected in the AVL constructs specially in central zones (p <0.0001). The immunohistological analysis showed a significant increase in the absolute expression of HIF-1 in the AVL group in comparison to the non-AVL group. The PCR analysis confirmed a 1.4-fold increase in HIF-1 expression in AVL constructs. Although PCR analysis showed an enhanced expression of CXCR4 and CXCR7 in AVL constructs, no significant differences in SDF1 expression were detected via immunohistological or PCR analysis. At the examined time point, the AVL constructs can attract BMMNCs in a mechanism probably related to the hypoxia associated with a robust tissue formation.

Project description:Treatment of acute myocardial infarction with stem cell transplantation has achieved beneficial effects in many clinical trials. The bone marrow microenvironment of ST-elevation myocardial infarction (STEMI) patients has never been studied even though myocardial infarction is known to cause an imbalance in the acid-base status of these patients. The aim of this study was to assess if the blood gas levels in the bone marrow of STEMI patients affect the characteristics of the bone marrow cells (BMCs) and, furthermore, do they influence the change in cardiac function after autologous BMC transplantation. The arterial, venous and bone marrow blood gas concentrations were also compared.Blood gas analysis of the bone marrow aspirate and peripheral blood was performed for 27 STEMI patients receiving autologous stem cell therapy after percutaneous coronary intervention. Cells from the bone marrow aspirate were further cultured and the bone marrow mesenchymal stem cell (MSC) proliferation rate was determined by MTT assay and the MSC osteogenic differentiation capacity by alkaline phosphatase (ALP) activity assay. All the patients underwent a 2D-echocardiography at baseline and 4 months after STEMI.As expected, the levels of pO(2), pCO(2), base excess and HCO(3) were similar in venous blood and bone marrow. Surprisingly, bone marrow showed significantly lower pH and Na(+) and elevated K(+) levels compared to arterial and venous blood. There was a positive correlation between the bone marrow pCO(2) and HCO(3) levels and MSC osteogenic differentiation capacity. In contrast, bone marrow pCO(2) and HCO(3) levels displayed a negative correlation with the proliferation rate of MSCs. Patients with the HCO(3) level below the median value exhibited a more marked change in LVEF after BMC treatment than patients with HCO(3) level above the median (11.13 ± 8.07% vs. 2.67 ± 11.89%, P = 0.014).Low bone marrow pCO(2) and HCO(3) levels may represent the optimal environment for BMCs in terms of their efficacy in autologous stem cell therapy in STEMI patients.

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Preservation of myocardial structure is enhanced by pim-1 engineering of bone marrow cells.

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Preservation of myocardial structure is enhanced by pim-1 engineering of bone marrow cells.

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