Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury

Hsieh, Patrick C.; Segers, Vincent F.M.; Davis, Michael; MacGillivray, Catherine; Gannon, Joseph; Molkentin, Jeffery D.; Robbins, Jeffrey; Lee, Richard T.

doi:10.1038/nm1618

Cited by 708 publications

(643 citation statements)

References 16 publications

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“…To more specifically address whether endogenous myocardial-derived ST2 signaling regulates pressure overload-induced cardiac hypertrophy, we generated mice for conditional deletion of the ST2 gene. A cardiomyocyte-specific ST2 deletion mouse was generated by cross-breeding ST2 fl/fl mice with myh6-mER-Cre-mER/ZEG double transgenic mice (21) to obtain ST2 fl/fl / mER-Cre-mER/ZEG mice, in which cardiomyocyte-specific inducible Cre was driven by the myh6 promoter in cardiomyocytes and in which the ZEG reporter could be monitored as a marker of Cre recombination. Before 4-OH tamoxifen induction, cardiomyocytes expressed the LacZ and ST2 genes.…”

Section: Significancementioning

confidence: 99%

Myocardial pressure overload induces systemic inflammation through endothelial cell IL-33

Chen

Hong

Gannon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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132

125

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Hypertension increases the pressure load on the heart and is associated with a poorly understood chronic systemic inflammatory state. Interleukin 33 (IL-33) binds to membrane-bound ST2 (ST2L) and has antihypertrophic and antifibrotic effects in the myocardium. In contrast, soluble ST2 appears to act as a decoy receptor for IL-33, blocking myocardial and vascular benefits, and is a prognostic biomarker in patients with cardiovascular diseases. Here we report that a highly local intramyocardial IL-33/ST2 conversation regulates the heart's response to pressure overload. Either endothelial-specific deletion of IL33 or cardiomyocyte-specific deletion of ST2 exacerbated cardiac hypertrophy with pressure overload. Furthermore, pressure overload induced systemic circulating IL-33 as well as systemic circulating IL-13 and TGF-beta1; this was abolished by endothelial-specific deletion of IL33 but not by cardiomyocyte-specific deletion of IL33. Our study reveals that endothelial cell secretion of IL-33 is crucial for translating myocardial pressure overload into a selective systemic inflammatory response.H ypertension is the most common cardiovascular risk factor and contributes to widespread morbidity and mortality worldwide (1), but the pathological and molecular mechanisms by which elevated blood pressure promotes vascular disease remain uncertain. Inflammation has been hypothesized to play a role in hypertension as well as the progression of vascular disease (2, 3). Although the association between hypertension and inflammation has now been clearly demonstrated, molecular mechanisms that link hypertension to systemic inflammation are unclear.The soluble receptor ST2 is a prognostic biomarker in patients with cardiovascular disease (4, 5), and serum ST2 levels also predict changes in blood pressure in the community (6). ST2, also known as IL1RL1 (IL-1 receptor like 1), is a member of the IL-1 receptor family, which plays a major role in immune and inflammatory responses (7). At least two forms of ST2 are known, including the transmembrane receptor (ST2L) and the soluble form (sST2) that circulates in blood (8). Membrane-bound ST2L interacts with IL-33, an IL-1 family ligand (9), and IL-33 can have antihypertrophic and antifibrotic effects in the myocardium (10). In contrast, sST2 appears to act as a decoy receptor for IL-33, blocking myocardial and vascular benefits (10-12). IL-33 is also expressed in endothelial cells (ECs) (13-16), in which it induces angiogenesis (17), expression of adhesion molecules, and inflammatory activation (18). Here we report the surprising finding that endothelial IL-33 from pressure overload induces a selective systemic response, potentially linking hypertension with circulating factors that can affect the vasculature and other organs. Results ST2 Deficiency Exacerbates Pressure Overload-Induced CardiacHypertrophy. Communication between cardiomyocytes, fibroblasts, and ECs is important for normal cardiac function as well as pathophysiology (19,20). We explored intercellular communication in...

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Section: Significancementioning

confidence: 99%

Myocardial pressure overload induces systemic inflammation through endothelial cell IL-33

Chen

Hong

Gannon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

132

125

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“…However, differentiation of these cells is rare under physiological conditions [48]. For therapeutic purposes, CSCs can be generated by expanding autologous cells ex vivo or stimulating the regeneration capacity of these cells in vivo.…”

Section: Heart Injurymentioning

confidence: 99%

Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration

Glaser

Cappellari

Pillat

et al. 2011

Purinergic Signalling

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Replacement of lost or dysfunctional tissues by stem cells has recently raised many investigations on therapeutic applications. Purinergic signaling has been shown to regulate proliferation, differentiation, cell death, and successful engraftment of stem cells originated from diverse origins. Adenosine triphosphate release occurs in a controlled way by exocytosis, transporters, and lysosomes or in large amounts from damaged cells, which is then subsequently degraded into adenosine. Paracrine and autocrine mechanisms induced by immune responses present critical factors for the success of stem cell therapy. While P1 receptors generally exert beneficial effects including anti-inflammatory activity, P2 receptor-mediated actions depend on the subtype of stimulated receptors and localization of tissue repair. Pro-inflammatory actions and excitatory tissue damages mainly result from P2X7 receptor activation, while other purinergic receptor subtypes participate in proliferation and differentiation, thereby providing adequate niches for stem cell engraftment and novel mechanisms for cell therapy and endogenous tissue repair. Therapeutic applications based on regulation of purinergic signaling are foreseen for kidney and heart muscle regeneration, Clara-like cell replacement for pulmonary and bronchial epithelial cells as well as for induction of neurogenesis in case of neurodegenerative diseases.

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“…These stem cells express cKit, Sca-1 and MDR1 and are clonogenic in vitro, able to produce cardiomyocytes, endothelia and smooth muscle cells from single cells. A contribution of undifferentiated stem/progenitor cells to the repair of the murine heart after myocardial infarction has been elegantly shown [147].…”

Section: Heartmentioning

confidence: 99%

Attributes of adult stem cells

Alison

Islam

2008

The Journal of Pathology

151

115

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While cultured embryonic stem (ES) cells can be harvested in abundance and appear to be the most versatile of cells for regenerative medicine, adult stem cells also hold promise, but the identity and subsequent isolation of these comparatively rare cells remains problematic in most tissues, perhaps with the notable exception of the bone marrow. The ability to continuously self-renew and produce the differentiated progeny of the tissue of their location are their defining properties. Identifying surface molecules (markers) that would aid in stem cell isolation is a major goal. Considerable overlap exists between different putative organspecific stem cells in their repertoire of gene expression, often related to self-renewal, cell survival and cell adhesion. More robust tests of 'stemness' are now being employed, using lineage-specific genetic marking and tracking to show production of long-lived clones and multipotentiality in vivo. Moreover, the characterization of normal stem cells in specific tissues may provide a dividend for the treatment of cancer. The successful treatment of neoplastic disease may well require the specific targeting of neoplastic stem cells, cells that may well have many of the characteristics of their normal counterparts.

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Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury

Cited by 708 publications

References 16 publications

Myocardial pressure overload induces systemic inflammation through endothelial cell IL-33

Myocardial pressure overload induces systemic inflammation through endothelial cell IL-33

Perspectives of purinergic signaling in stem cell differentiation and tissue regeneration

Attributes of adult stem cells

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