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Interrupted reprogramming of Alveolar Type II cells induces progenitor-like cells that ameliorate pulmonary fibrosis

ABSTRACT: We describe here an interrupted reprogramming strategy to generate "induced Progenitor-Like (iPL) cells" from Alveolar Epithelial Type II (AEC-II) cells. A carefully defined period of transient expression of reprogramming factors (Oct4, Sox2, Klf4 and c-Myc; OSKM) is able to rescue the limited in vitro clonogenic capacity of AEC-II cells, potentially by activation of a bipotential progenitor-like state. Microarray analysis of genome-wide transcriptional changes showed the ability of AEC-II-iPL cells to return to the original phenotype

ORGANISM(S): Mus musculus

PROVIDER: GSE115247 | GEO | 2018/09/26

REPOSITORIES: GEO

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Generation of induced progenitor-like cells from mature epithelial cells using interrupted reprogramming

Project description:A suitable source of progenitor cells is required to attenuate disease or affect cure. We present a novel interrupted reprogramming strategy to generate induced Progenitor-Like (iPL) cells using carefully timed -expression of induced Pluripotent Stem cell reprogramming factors (Oct4, Sox2, Klf4 and c-Myc; OSKM) from non-proliferative Club cells. Interrupted reprogramming allowed controlled expansion yet preservation of lineage commitment. Under clonogenic conditions, iPL cells expanded and functioned as a bronchiolar progenitor-like population to generate mature Club cells, mucin-producing goblet cells, and CFTR-expressing ciliated epithelium. In vivo, iPL cells can repopulate CFTR-deficient epithelium. This interrupted reprogramming process could be metronomically applied, to achieve controlled progenitor-like proliferation. By carefully controlling the duration of -expression of OSKM, iPL cells don't become pluripotent and maintain their memory of origin and retain their ability to efficiently return to their original phenotype. A generic technique to produce highly specified populations may have significant implications for regenerative medicine. Microarray analysis of genome-wide transcriptional changes showed Club-iPL cells have minimal expression of ES cell-related genes (e.g. Nanog, Utf1, Dapp4) and maintained significant overlapping expression of Club cell-related genes. Further analysis showed that the expression of large numbers of genes temporally changed during Dox-driven expansion of Club cells but returned upon withdrawal of the factors.

2017-10-24 | GSE105775 | GEO

Interrupted reprogramming of Alveolar Type II cells induces progenitor-like cells that ameliorate pulmonary fibrosis

Project description:Interrupted reprogramming of Alveolar Type II cells induces progenitor-like cells that ameliorate pulmonary fibrosis

| PRJNA474235 | ENA

Generation of induced progenitor-like cells from mature epithelial cells using interrupted reprogramming

Project description:Generation of induced progenitor-like cells from mature epithelial cells using interrupted reprogramming

| PRJNA415379 | ENA

Quantitative Analysis of Proteome Modulations in Alveolar Epithelial Type II Cells in Response to Pulmonary Aspergillus fumigatus Infection

Project description:We established a new protocol for negative immunomagnetic isolation of murine primary Type II alveolar epithelial cells (AEC II) yielding untouched primary murine AEC II. AEC II were collected from mice 24h after Aspergillus fumigatus or mock infection (9 replicates per experimental group) and analyzed by label-free quantitative proteomics.

2017-10-05 | PXD005834 | Pride

OSKM induce extraembryonic endoderm stem (iXEN) cells in parallel to iPS cells

Project description:While the reprogramming factors OCT4, SOX2, KLF4, and MYC (OSKM) can reactivate the pluripotency network in terminally differentiated cells, they also regulate expression of non-pluripotency genes in other contexts, such as the mouse primitive endoderm. The primitive endoderm is an extraembryonic lineage established alongside the pluripotent epiblast in the blastocyst, and is the progenitor pool for extraembryonic endoderm stem (XEN) cells. Several studies have shown that endodermal genes are upregulated in fibroblasts undergoing reprogramming, although whether endodermal genes promote or inhibit acquisition of pluripotency is unclear. We show that, in fibroblasts undergoing conventional reprogramming, OSKM-induced expression of endodermal genes leads to formation of induced XEN (iXEN) cells, which possess key properties of blastocyst-derived XEN cells, including morphology, transcription profile, self-renewal, and multipotency. Our data show that iXEN cells arise in parallel to iPS cells, indicating that OSKM are sufficient to drive cells to two distinct fates during reprogramming. Sequence-based mRNA transcriptional profiling of three different cell lines (MEF, XEN, iXEN) with multiple biological replicates, under two different growth medium conditions (ESC medium, XEN medium) for XEN and iXEN cells.

2016-03-03 | E-GEOD-77550 | biostudies-arrayexpress

Interrupted reprogramming into induced pluripotent stem cells does not rejuvenate human mesenchymal stromal cells

Project description:Interrupted reprogramming into induced pluripotent stem cells does not rejuvenate human mesenchymal stromal cells

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Transcription profiling of mouse bipotential embryonic liver cells to identify liver progenitor cell surface markers.

Project description:This SuperSeries is composed of the following subset Series:; GSE6942: Transcriptional profiling of bipotential embryonic liver cells to identify liver progenitor cell surface markers (moe430a). GSE6957: Transcriptional profiling of bipotential embryonic liver cells to identify liver progenitor cell surface markers (mouse4302). Experiment Overall Design: Refer to individual Series

2008-06-15 | E-GEOD-6966 | biostudies-arrayexpress

OSKM induce extraembryonic endoderm stem (iXEN) cells in parallel to iPS cells

2016-03-03 | GSE77550 | GEO

Transcriptional Pause Release Is a Rate-Limiting Step for Somatic Cell Reprogramming (ChIP-seq)

Project description:Reactivation of the pluripotency network during somatic cell reprogramming by exogenous transcription factors involves chromatin remodeling and the recruitment of RNA polymerase II (Pol II) to target loci. Here, we report that Pol II is engaged at pluripotency promoters in reprogramming but remains paused and inefficiently released. We also show that bromodomain-containing protein 4 (BRD4) stimulates productive transcriptional elongation of pluripotency genes by dissociating the pause release factor P-TEFb from an inactive complex containing HEXIM1. Consequently, BRD4 overexpression enhances reprogramming efficiency and HEXIM1 suppresses it, whereas Brd4 and Hexim1 knockdown do the opposite. We further demonstrate that the reprogramming factor KLF4 helps recruit P-TEFb to pluripotency promoters. Our work thus provides a mechanism for explaining the reactivation of pluripotency genes in reprogramming and unveils an unanticipated role for KLF4 in transcriptional pause release. Pol II ChIP-seq for MEFs, ESCs and bulk populations of OSKM reprogramming intermediates at two time points.

2014-10-07 | E-GEOD-59828 | biostudies-arrayexpress

Human transcription factors responsive to initial reprogramming are predominantly legitimate during iPSC reprogramming

Project description:The four transcription factors OCT4, SOX2, KLF4 and MYC (OSKM) together can convert human fibroblasts to induced pluripotent stem cells (iPSCs). It is, however, perplexing that they can do so only for a rare population of the starting cells with a long latency. Transcription factors (TFs) define identities of both the starting fibroblasts and the end product, iPSCs, and are of paramount importance for the reprogramming process as well. It is critical to upregulate or activate iPSC-enriched TFs while downregulate or silence the fibroblast-enriched TFs. This report explores the initial TF responses to OSKM as the molecular underpinnings for both the potency aspect and limitation sides of the OSKM reprogramming. The author first defined the TF reprogramome, i.e., the full complement of TFs to be reprogrammed. Most TFs were resistant to OSKM reprogramming at the initial stages, which agrees with the inefficiency and long latency of iPSC reprogramming. Surprisingly, the current analyses revealed that the majority of the TFs (83 genes) that did respond to OSKM induction underwent legitimate reprogramming. The initial legitimate transcriptional responses of TFs to OSKM reprogramming were observed from fibroblasts from a different individual. Such early biased legitimate reprogramming of the responsive TFs aligns well with the robustness aspect of the otherwise inefficient and stochastic OSKM reprogramming

2020-12-08 | GSE159410 | GEO

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