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Cells expressing early cardiac markers reside in the bone marrow and are mobilized into the peripheral blood after myocardial infarction.

ABSTRACT: The concept that bone marrow (BM)-derived cells participate in cardiac regeneration remains highly controversial and the identity of the specific cell type(s) involved remains unknown. In this study, we report that the postnatal BM contains a mobile pool of cells that express early cardiac lineage markers (Nkx2.5/Csx, GATA-4, and MEF2C). These cells are present in significant amounts in BM harvested from young mice but their abundance decreases with age; in addition, the responsiveness of these cells to gradients of motomorphogens SDF-1, HGF, and LIF changes with age. FACS analysis, combined with analysis of early cardiac markers at the mRNA and protein levels, revealed that cells expressing these markers reside in the nonadherent, nonhematopoietic CXCR4+/Sca-1+/lin-/CD45- mononuclear cell (MNC) fraction in mice and in the CXCR4+/CD34+/AC133+/CD45- BMMNC fraction in humans. These cells are mobilized into the peripheral blood after myocardial infarction and chemoattracted to the infarcted myocardium in an SDF-1-CXCR4-, HGF-c-Met-, and LIF-LIF-R-dependent manner. To our knowledge, this is the first demonstration that the postnatal BM harbors a nonhematopoietic population of cells that express markers for cardiac differentiation. We propose that these potential cardiac progenitors may account for the myocardial regenerative effects of BM. The present findings provide a novel paradigm that could reconcile current controversies and a rationale for investigating the use of BM-derived cardiac progenitors for myocardial regeneration.

SUBMITTER: Kucia M

PROVIDER: S-EPMC3679649 | biostudies-literature | 2004 Dec

REPOSITORIES: biostudies-literature

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Cells expressing early cardiac markers reside in the bone marrow and are mobilized into the peripheral blood after myocardial infarction.

Kucia Magda M Dawn Buddhadeb B Hunt Greg G Guo Yiru Y Wysoczynski Marcin M Majka Marcin M Ratajczak Janina J Rezzoug Francine F Ildstad Suzanne T ST Bolli Roberto R Ratajczak Mariusz Z MZ

Circulation research 20041118 12

The concept that bone marrow (BM)-derived cells participate in cardiac regeneration remains highly controversial and the identity of the specific cell type(s) involved remains unknown. In this study, we report that the postnatal BM contains a mobile pool of cells that express early cardiac lineage markers (Nkx2.5/Csx, GATA-4, and MEF2C). These cells are present in significant amounts in BM harvested from young mice but their abundance decreases with age; in addition, the responsiveness of these ...[more]

PMID: 15550692

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Project description:Our previous study shows that treatment with apelin increases bone marrow cells (BMCs) recruitment and promotes cardiac repair after myocardial infarction (MI). The objective of this study was to investigate whether overexpression of apelin in BMCs improved cell therapy and accelerated cardiac repair and functional recovery in post-MI mice. Mouse myocardial infarction was achieved by coronary artery ligation and BMCs overexpressing apelin (apelin-BMCs) or GFP (GFP-BMCs) were injected into ischemic area immediately after surgery. In vitro, exposure of cultured BMCs to apelin led to a gradual increase in SDF-1á and CXCR4 expression. Intramyocardial delivery of apelin-BMCs in post-MI mice resulted in a significant increase number of APJ?/c-kit?/Sca1? cells in the injected area compared to GFP-BMCs treated post-MI mice. Treatment with apelin-BMCs increased expression of VEGF, Ang-1 and Tie-2 in post-MI mice. Apelin-BMCs treatment also significantly increased angiogenesis and attenuated cardiac fibrosis formation in post-MI mice. Most importantly, treatment with apelin-BMCs significantly improved left ventricular (LV) systolic function in post-MI mice. Mechanistically, Apelin-BMCs treatment led to a significant increase in Sirtuin3 (Sirt3) expression and reduction of reactive oxygen species (ROS) formation. Treatment of cultured BMCs with apelin also increased Notch3 expression and Akt phosphorylation. Apelin treatment further attenuated stress-induced apoptosis whereas knockout of Sirt3 abolished anti-apoptotic effect of apelin in cultured BMCs. Moreover, knockout of Sirt3 significantly attenuated apelin-BMCs-induced VEGF expression and angiogenesis in post-MI mice. Knockout of Sirt3 further blunted apelin-BMCs-mediated improvement of cardiac repair and systolic functional recovery in post-MI mice. These data suggest that apelin improves BMCs therapy on cardiac repair and systolic function in post-MI mice. Upregulation of Sirt3 may contribute to the protective effect of apelin-BMCs therapy.

Project description:AimsRetinoic acid receptor-related orphan nuclear receptor ?t (ROR?t) is a transcriptional factor responsible for IL-17-producing T-cell differentiation. Although it was demonstrated that ROR?t plays essential roles in the onset of autoimmune myocarditis, pathophysiological significance of ROR?t in cardiac remodeling after myocardial infarction (MI) remains to be fully elucidated.Methods and resultsMI was generated by ligating coronary artery. The expression of ROR?t and IL-17A transcripts increased in murine hearts after MI. Additionally, immunohistochemical staining revealed that ROR?t-expressing cells infiltrated in the border zone after MI. Flow cytometric analysis showed that ROR?t-expressing cells were released from the spleen at day 1 after MI. Though ROR?t-expressing cells in spleen expressed ??TCR or CD4, ??TCR+ cells were major population of ROR?t-expressing cells that infiltrated into post-infarct myocardium. To address the biological functions of ROR?t-expressing cells in infarcted hearts, we used mice with enhanced GFP gene heterozygously knocked-in at ROR?t locus (ROR?t+/- mice), which physiologically showed reduced expression of ROR?t mRNA in thymus. Kaplan-Meier analysis showed that MI-induced mortality was higher in ROR?t+/- mice than wild-type (WT) mice. Masson's trichrome staining demonstrated that cardiac injury was exacerbated in ROR?t+/- mice 7 days after MI (Injured area: ROR?t+/-; 42.1±6.5%, WT; 34.0±3.7%, circumference of injured myocardium: ROR?t+/-; 61.8±4.8%, WT; 49.6±5.1%), accompanied by exacerbation of cardiac function (fractional shortening: ROR?t+/-; 32.9±2.9%, WT; 38.3±3.6%). Moreover, immunohistochemical analyses revealed that capillary density in border zone was significantly reduced in ROR?t+/- mice after MI, compared with WT mice, associated with the reduced expression of angiopoietin 2. Finally, the mRNA expression of ROR?t, IL-17A, IL-17F and IL-23 receptor (IL-23R) mRNA and protein expression of IL-10 were decreased in ROR?t+/- hearts.ConclusionsHeterozygous deletion of ROR?t gene resulted in aggravated cardiac remodeling, accompanied by reduced capillary density, after MI, suggesting that ROR?t-expressing cells contribute to tissue repair in infarcted myocardium.

Project description:RationaleIntracoronary infusion of bone marrow (BM) mononuclear cells after acute myocardial infarction (AMI) has led to limited improvement in left ventricular function. Although experimental AMI models have implicated cytokine-related impairment of progenitor cell function, this response has not been investigated in humans.ObjectiveTo test the hypothesis that peripheral blood (PB) cytokines predict BM endothelial progenitor cell colony outgrowth and cardiac function after AMI.Methods and resultsBM and PB samples were collected from 87 participants 14 to 21 days after AMI and BM from healthy donors was used as a reference. Correlations between cytokine concentrations and cell phenotypes, cell functions, and post-AMI cardiac function were determined. PB interleukin-6 (IL-6) negatively correlated with endothelial colony-forming cell colony maximum in the BM of patients with AMI (estimate±SE, -0.13±0.05; P=0.007). BM from healthy individuals showed a dose-dependent decrease in endothelial colony-forming cell colony outgrowth in the presence of exogenous IL-1β or IL-6 (P<0.05). Blocking the IL-1R or IL-6R reversed cytokine impairment. In AMI study participants, the angiogenic cytokine platelet-derived growth factor BB glycoprotein correlated positively with BM-derived colony-forming unit-endothelial colony maximum (estimate±SE, 0.01±0.002; P<0.001), multipotent mesenchymal stromal cell colony maximum (estimate±SE, 0.01±0.002; P=0.002) in BM, and mesenchymal stromal cell colony maximum in PB (estimate±SE, 0.02±0.005; P<0.001).ConclusionsTwo weeks after AMI, increased PB platelet-derived growth factor BB glycoprotein was associated with increased BM function, whereas increased IL-6 was associated with BM impairment. Validation studies confirmed inflammatory cytokine impairment of BM that could be reversed by blocking IL-1R or IL-6R. Together, these studies suggest that blocking IL-1 or IL-6 receptors may improve the regenerative capacity of BM cells after AMI.Clinical trial registrationsURL: http://www.clinicaltrials.gov. Unique identifier: NCT00684060.

Dataset Information

Cells expressing early cardiac markers reside in the bone marrow and are mobilized into the peripheral blood after myocardial infarction.

Publications

Cells expressing early cardiac markers reside in the bone marrow and are mobilized into the peripheral blood after myocardial infarction.

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