HDAC activity regulates entry of mesoderm cells into the cardiac muscle lineage

Karamboulas, Christina; Swedani, Albert; Ward, Chris; Madhoun, Ashraf Al; Wilton, Sharon; Boisvenue, Sophie; Ridgeway, Alan G.; Skerjanc, Ilona S.

doi:10.1242/jcs.03185

Cited by 100 publications

(95 citation statements)

References 89 publications

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“…In contrast, overexpression of HDAC4 antagonized this event, indicating that the suppression of HDAC4 of CSCs is required for cardiac lineage commitment in vivo. This is supported by a previous observation that the overexpression of HDAC4 inhibited cardiomyogenesis, shown by the downregulation of cardiac muscle genes in P19 cells (21). Activation of HDAC4 suppresses MEF2-dependent gene expression and contributes to progressive muscle dysfunction observed in neuromuscular diseases (7).…”

Section: Discussionsupporting

confidence: 76%

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Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

Zhang

DeNicola

Qin

et al. 2014

American Journal of Physiology-Cell Physiology

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We have recently shown that in vivo inhibition of histone deacetylase (HDAC) stimulates endogenous myocardial regeneration in infarcted hearts (Zhang L et al. J Pharmacol Exp Ther 341: 285-293, 2012). Furthermore, our observation demonstrates that HDAC inhibition promotes cardiogenesis, which is associated with HDAC4 reduction. However, it remains unknown as to whether specific inhibition of HDAC4 modulates cardiac stem cells (CSCs) to facilitate myocardial repair and to preserve cardiac performance. c-kit ϩ CSCs were isolated from adult mouse hearts and were transfected with HDAC4 siRNA to knockdown HDAC4 of c-kit ϩ CSCs. The transfection of HDAC4 siRNA caused a marked reduction of HDAC4 mRNA and proteins in c-kit ϩ CSCs. Mouse myocardial infarction (MI) was created to assess the effect of HDAC4 inhibition in c-kit ϩ CSCs on myocardial regeneration in vivo when cells were introduced into MI hearts. Transplantation of HDAC4 siRNA-treated c-kit ϩ CSCs into MI hearts improved ventricular function, attenuated ventricular remodeling, and promoted CSC-derived regeneration and neovascularization. Furthermore, Ki67 and BrdU positively proliferative myocytes increased in MI hearts receiving HDAC4 siRNA-treated c-kit ϩ CSCs compared with MI hearts engrafted with control siRNA-treated c-kit ϩ CSCs. In addition, compared with MI hearts engrafted with control adenoviral GFPinfected c-kit ϩ CSCs, MI hearts receiving adenoviral HDAC4-infected c-kit ϩ CSCs exhibited attenuated cardiac functional recovery, CSC-derived regeneration, and neovascularization, which was accompanied with adverse ventricular remodeling and decrease in Ki67 and BrdU positively proliferative myocytes. HDAC4 inhibition facilitated c-kit ϩ CSCs into the differentiation into cardiac lineage commitments in vitro, while HDAC4 overexpression attenuated c-kit ϩ CSC-derived cardiogenesis. Our results indicate that HDAC4 inhibition promotes CSC-derived cardiac regeneration and improves the restoration of cardiac function.heart; HDAC4; regeneration; myocardial infarction; stem cells IT HAS NOW BEEN RECOGNIZED that adult hearts harbor distinct populations of cardiac progenitors (2,25,26,34), which have the potential to differentiate into cardiomyocytes, endothelia, and vascular smooth muscle cells. Furthermore, several studies have shown that these cardiac progenitor cells are capable of differentiating into cardiac tissue and improving cardiac function after a myocardial injury. Exponential advances in stem cell and regenerative biology are beginning to foster a transition toward therapeutic goals for cardiac regenerative medicine (8,14,15,33). However, poor cell viability, proliferation, and inefficient differentiation following transplantation have limited the reparative capacity of these cells in vivo (26,29,39). Thus molecular intervention strategies to enhance cardiac stem cell (CSC) proliferation and survival hold dramatic consequences for enhancing myogenesis and will empower therapeutically relevant implementation of myocardial regeneration. It was repor...

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Section: Discussionsupporting

confidence: 76%

“…HDAC4 is expressed in the heart, stem cells, the endothelium, and vascular smooth muscle cells (1,4,12,19,21). Cardioprotective effects of HDAC inhibition against injury have been well identified (45,47,48).…”

mentioning

confidence: 99%

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

Zhang

DeNicola

Qin

et al. 2014

American Journal of Physiology-Cell Physiology

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“…In particular, HDAC4 and -5 are regulated through CaMKII or CaMKIV, 46 -50 and this is required for the expression of early cardiac genes such as Nkx2.5, MEF2C, or GATA-4. 46 This would not only provide an additional link to gene regulation through noncanonical Wnt signaling but suggests that a misregulation of noncanonical Wnt signaling could result in pathophysiological conditions in the heart that had been linked to CaMKII or HDACs. 48,51 One interesting finding here is that noncanonical Wnt signaling has been shown to modulate the activity of a histone lysine methyltransferase in a different setting.…”

Section: ␤-Catenin-independent Noncanonical Wnt Pathwaysmentioning

confidence: 99%

An Updated Overview on Wnt Signaling Pathways

Tata

Kühl

2010

Circulation Research

601

502

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Growth factor signaling is required for cellular differentiation, tissue morphogenesis, and tissue homeostasis.Misregulation of intracellular signal transduction can lead to developmental defects during embryogenesis or particular diseases in the adult. One family of growth factors important for these aspects is given by the Wnt proteins. In particular, Wnts have important functions in stem cell biology, cardiac development and differentiation, angiogenesis, cardiac hypertrophy, cardiac failure, and aging. Knowledge of growth factor signaling during differentiation will allow for improvement of targeted differentiation of embryonic or adult stem cells toward functional cardiomyocytes or for understanding the basis of diseases. Our major aim here is to provide a state of the art review summarizing our present knowledge of the intracellular Wnt-mediated signaling network. In particular, we provide evidence that the subdivision into canonical and noncanonical Wnt signaling pathways solely based on the identity of Wnt ligands or Frizzled receptors is not appropriate anymore. We thereby deliver a solid base for further upcoming articles of a review series focusing on the role of Wnt proteins on different aspects of cardiovascular development and dysfunction.

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“…The class II HDACs: HDAC4, HDAC5, HDAC6, HDAC7, HDAC9 and HDAC10 contain both nuclear localisation and export signals, trafficking between the cytoplasm and nucleus (Wang and Yang, 2001). Class II HDACs are reported to be important for cell differentiation in tissues such as muscles (Deng et al, 2005;Dressel et al, 2001;Karamboulas et al, 2006;Lu et al, 2000;McKinsey et al, 2000;McKinsey et al, 2001;Miyake et al, 2003;Vega et al, 2004;Zhang et al, 2002). HDAC7 is a member of the human class II HDAC family.…”

Section: Introductionmentioning

confidence: 99%

Splicing of HDAC7 modulates the SRF-myocardin complex during stem-cell differentiation towards smooth muscle cells

Margariti

Xiao

Zampetaki

et al. 2009

Journal of Cell Science

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Histone deacetylases (HDACs) have a central role in the regulation of gene expression. Here we investigated whether HDAC7 has an impact on embryonic stem (ES) cell differentiation into smooth muscle cells (SMCs). ES cells were seeded on collagen-IV-coated flasks and cultured in the absence of leukemia inhibitory factor in differentiation medium to induce SMC differentiation. Western blots and double-immunofluorescence staining demonstrated that HDAC7 has a parallel expression pattern with SMC marker genes. In ex vivo culture of embryonic cells from SM22-LacZ transgenic mice, overexpression of HDAC7 significantly increased β-galactosidase-positive cell numbers and enzyme activity, indicating its crucial role in SMC differentiation during embryonic development. We found that HDAC7 undergoes alternative splicing during ES cell differentiation. Platelet-derived growth factor enhanced ES cell differentiation into SMCs through upregulation of HDAC7 splicing. Further experiments revealed that HDAC7 splicing induced SMC differentiation through modulation of the SRF-myocardin complex. These findings suggest that HDAC7 splicing is important for SMC differentiation and vessel formation in embryonic development.

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HDAC activity regulates entry of mesoderm cells into the cardiac muscle lineage

Cited by 100 publications

References 89 publications

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

An Updated Overview on Wnt Signaling Pathways

Splicing of HDAC7 modulates the SRF-myocardin complex during stem-cell differentiation towards smooth muscle cells

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