Dataset Information

Development and regeneration of Sox2+ endoderm progenitors are regulated by a Hdac1/2-Bmp4/Rb1 regulatory pathway.

ABSTRACT: The mechanisms that govern the maintenance and differentiation of tissue-specific progenitors in development and tissue regeneration are poorly understood. We show that development of Sox2+ progenitors in the lung endoderm is regulated by histone deacetylases 1 and 2 (Hdac1/2). Hdac1/2 deficiency leads to a loss of Sox2 expression and a block in proximal airway development. This is mediated in part by derepression of Bmp4 and the tumor suppressor Rb1, which are direct transcriptional targets of Hdac1/2. In contrast to development, postnatal loss of Hdac1/2 in airway epithelium does not affect the expression of Sox2 or Bmp4. However, postnatal loss of Hdac1/2 leads to increased expression of the cell-cycle regulators Rb1, p21/Cdkn1a, and p16/Ink4a, resulting in a loss of cell-cycle progression and defective regeneration of Sox2+ lung epithelium. Thus, Hdac1/2 have both common and unique targets that differentially regulate tissue-specific progenitor activity during development and regeneration.

SUBMITTER: Wang Y

PROVIDER: S-EPMC3586315 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Publications

Development and regeneration of Sox2+ endoderm progenitors are regulated by a Hdac1/2-Bmp4/Rb1 regulatory pathway.

Wang Yi Y Tian Ying Y Morley Michael P MP Lu Min M MM Demayo Francesco J FJ Olson Eric N EN Morrisey Edward E EE

Developmental cell 20130201 4

The mechanisms that govern the maintenance and differentiation of tissue-specific progenitors in development and tissue regeneration are poorly understood. We show that development of Sox2+ progenitors in the lung endoderm is regulated by histone deacetylases 1 and 2 (Hdac1/2). Hdac1/2 deficiency leads to a loss of Sox2 expression and a block in proximal airway development. This is mediated in part by derepression of Bmp4 and the tumor suppressor Rb1, which are direct transcriptional targets of ...[more]

PMID: 23449471

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Project description:As heart failure due to myocardial infarction remains a leading cause of morbidity worldwide, cell-based cardiac regenerative therapy using cardiac progenitor cells (CPCs) could provide a potential treatment for the repair of injured myocardium. As adult CPCs may have limitations regarding tissue accessibility and proliferative ability, CPCs derived from embryonic stem cells (ESCs) could serve as an unlimited source of cells with high proliferative ability. As one of the CPCs that can be derived from embryonic stem cells, Isl1 expressing cardiac progenitor cells (Isl1-CPCs) may serve as a valuable source of cells for cardiac repair due to their high cardiac differentiation potential and authentic cardiac origin. In order to generate an unlimited number of Isl1-CPCs, we used a previously established an ESC line that allows for isolation of Isl1-CPCs by green fluorescent protein (GFP) expression that is directed by the mef2c gene, specifically expressed in the Isl1 domain of the anterior heart field. To improve the efficiency of cardiac differentiation of Isl1-CPCs, we studied the role of Bmp4 in cardiogenesis of Isl1-CPCs. We show an inductive role of Bmp directly on cardiac progenitors and its enhancement on early cardiac differentiation of CPCs. Upon induction of Bmp4 to Isl1-CPCs during differentiation, the cTnT+ cardiomyocyte population was enhanced 2.8±0.4 fold for Bmp4 treated CPC cultures compared to that detected for vehicle treated cultures. Both Bmp4 treated and untreated cardiomyocytes exhibit proper electrophysiological and calcium signaling properties. In addition, we observed a significant increase in Tbx5 and Tbx20 expression in differentiation cultures treated with Bmp4 compared to the untreated control, suggesting a link between Bmp4 and Tbx genes which may contribute to the enhanced cardiac differentiation in Bmp4 treated cultures. Collectively these findings suggest a cardiomyogenic role for Bmp4 directly on a pure population of Isl1 expressing cardiac progenitors, which could lead to enhancement of cardiac differentiation and engraftment, holding a significant therapeutic value for cardiac repair in the future.

Dataset Information

Development and regeneration of Sox2+ endoderm progenitors are regulated by a Hdac1/2-Bmp4/Rb1 regulatory pathway.

Publications

Development and regeneration of Sox2+ endoderm progenitors are regulated by a Hdac1/2-Bmp4/Rb1 regulatory pathway.

Similar Datasets

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