Inactivation of Smad5 in Endothelial Cells and Smooth Muscle Cells Demonstrates that Smad5 Is Required for Cardiac Homeostasis

Umans, Lieve; Cox, Luk; Tjwa, Marc; Bito, Virginie; Vermeire, Liesbeth; Laperre, Kjell; Sipido, Karin R.; Moons, Lieve; Huylebroeck, Danny; Zwijsen, An

doi:10.2353/ajpath.2007.060839

Cited by 43 publications

(29 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous analysis of the Tie-1-Cre line reveals extremely high specificity for endothelial cells throughout all organs examined, although some recombination has been noted in certain CNS neurons and hematopoietic cells (23)(24)(25)(26)(27). β-Cell replication was analyzed in control and CTGF e2COIN/e2COIN ;Tie-1-Cre embryos at E18.5 using immunohistochemistry to examine expression of phosphorylated histone H3 (pH3) and insulin.…”

Section: Resultsmentioning

confidence: 99%

Connective tissue growth factor acts within both endothelial cells and β cells to promote proliferation of developing β cells

Guney

Petersen

Boustani

et al. 2011

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

View full text Add to dashboard Cite

Type 1 and type 2 diabetes result from an absolute or relative reduction in functional β-cell mass. One approach to replacing lost β-cell mass is transplantation of cadaveric islets; however, this approach is limited by lack of adequate donor tissue. Therefore, there is much interest in identifying factors that enhance β-cell differentiation and proliferation in vivo or in vitro. Connective tissue growth factor (CTGF) is a secreted molecule expressed in endothelial cells, pancreatic ducts, and embryonic β cells that we previously showed is required for β-cell proliferation, differentiation, and islet morphogenesis during development. The current study investigated the tissue interactions by which CTGF promotes normal pancreatic islet development. We found that loss of CTGF from either endothelial cells or β cells results in decreased embryonic β-cell proliferation, making CTGF unique as an identified β cell-derived factor that regulates embryonic β-cell proliferation. Endothelial CTGF inactivation was associated with decreased islet vascularity, highlighting the proposed role of endothelial cells in β-cell proliferation. Furthermore, CTGF overexpression in β cells during embryogenesis using an inducible transgenic system increased islet mass at birth by promoting proliferation of immature β cells, in the absence of changes in islet vascularity. Together, these findings demonstrate that CTGF acts in an autocrine manner during pancreas development and suggest that CTGF has the potential to enhance expansion of immature β cells in directed differentiation or regeneration protocols.

show abstract

Section: Resultsmentioning

confidence: 99%

Connective tissue growth factor acts within both endothelial cells and β cells to promote proliferation of developing β cells

Guney

Petersen

Boustani

et al. 2011

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

View full text Add to dashboard Cite

show abstract

“…These defects are reminiscent of the angiogenesis defects seen in Bmpr2 knockdown and Eng and Alk1 null embryos, suggesting SMAD5 may be functioning in the same pathway. However, mice in which Smad5 is conditionally deleted in ECs slightly later in development are viable and do not have defects in the embryonic or adult vasculature (138). This indicates that there is functional compensation for loss of SMAD5 expression later in development.…”

Section: Part 2: Bmp Signaling In Vascular Development and Diseasementioning

confidence: 99%

BMP signaling in vascular development and disease

Lowery

Caestecker

2010

Cytokine & Growth Factor Reviews

121

124

View full text Add to dashboard Cite

Genetic and functional studies indicate that common components of the Bone Morphogenetic Protein (BMP) signaling pathway play critical roles in regulating vascular development in the embryo, and in promoting vascular homeostasis and disease in the adult. However, discrepancies between in vitro and in vivo findings, and distinct functional properties of the BMP signaling pathway in different vascular beds have led to controversies in the field that have been difficult to reconcile. This review attempts to clarify some of these issues by providing an up to date overview of the biology and genetics of BMP signaling relevant to the intact vasculature.

show abstract

“…To determine the population that is responsible for these morphogenetic defects, SM22-Cre, WT1 CreERT2 and Mef2c-Cre were applied to delete NFPs in cardiomyocytes, endothelial cells, CNCCs, epicardial cells and cells derived from the SHF, respectively. The deletion of NFPs in cardiomyocytes via SM22-Cre, which is expressed in cardiomyocytes at the early stage of heart development in addition to its expression in smooth muscle cells (Li et al, 1996;Umans et al, 2007;Stankunas et al, 2008), resulted in trabeculation defects with thicker trabeculae and a decreased number of trabeculae per unit length at E14.5 (supplementary material Fig. S2A,B), whereas NFP deletion mediated by Tie2-Cre, Wnt1-Cre or WT1 CreERT2 did not display any trabeculation defects (supplementary material Fig.…”

Section: Nfps Regulate Ventricular Trabeculation In a Cardiomyocyteaumentioning

confidence: 99%

Numb family proteins are essential for cardiac morphogenesis and progenitor differentiation

Zhao

Guo

et al. 2014

Development

View full text Add to dashboard Cite

Numb family proteins (NFPs), including Numb and numb-like (Numbl), are cell fate determinants for multiple progenitor cell types. Their functions in cardiac progenitor differentiation and cardiac morphogenesis are unknown. To avoid early embryonic lethality and study NFP function in later cardiac development, Numb and Numbl were deleted specifically in heart to generate myocardial doubleknockout (MDKO) mice. MDKOs were embryonic lethal and displayed a variety of defects in cardiac progenitor differentiation, cardiomyocyte proliferation, outflow tract (OFT) and atrioventricular septation, and OFT alignment. By ablating NFPs in different cardiac populations followed by lineage tracing, we determined that NFPs in the second heart field (SHF) are required for OFT and atrioventricular septation and OFT alignment. MDKOs displayed an SHF progenitor cell differentiation defect, as revealed by a variety of methods including mRNA deep sequencing. Numb regulated cardiac progenitor cell differentiation in an endocytosis-dependent manner. Studies including the use of a transgenic Notch reporter line showed that Notch signaling was upregulated in the MDKO. Suppression of Notch1 signaling in MDKOs rescued defects in p57 expression, proliferation and trabecular thickness. Further studies showed that Numb inhibits Notch1 signaling by promoting the degradation of the Notch1 intracellular domain in cardiomyocytes. This study reveals that NFPs regulate trabecular thickness by inhibiting Notch1 signaling, control cardiac morphogenesis in a Notch1-independent manner, and regulate cardiac progenitor cell differentiation in an endocytosis-dependent manner. The function of NFPs in cardiac progenitor differentiation and cardiac morphogenesis suggests that NFPs might be potential therapeutic candidates for cardiac regeneration and congenital heart diseases.

show abstract

Inactivation of Smad5 in Endothelial Cells and Smooth Muscle Cells Demonstrates that Smad5 Is Required for Cardiac Homeostasis

Cited by 43 publications

References 43 publications

Connective tissue growth factor acts within both endothelial cells and β cells to promote proliferation of developing β cells

Connective tissue growth factor acts within both endothelial cells and β cells to promote proliferation of developing β cells

BMP signaling in vascular development and disease

Numb family proteins are essential for cardiac morphogenesis and progenitor differentiation

Contact Info

Product

Resources

About