Biology subjects

Jian-Motamedi, F.

Publications and source records attributed to Jian-Motamedi, F..

3 recordsLinked to original sources

bioRxiv2023

In vitro differentiation of mouse pluripotent stem cells into glucocorticoid-producing adrenocortical cells

Directed differentiation of pluripotent stem cells into specialized cell types represents an invaluable tool for a wide range of applications. Here, we have exploited single-cell transcriptomic data to develop a step-wise in vitro differentiation system from mouse embryonic stem cells into adrenocortical cells. We show that during development the adrenal primordium is embedded in an extracellular matrix containing tenascin and fibronectin. Culturing cells on fibronectin during differentiation increased the expression of the steroidogenic marker NR5A1. Furthermore, 3D cultures in the presence of PKA-pathway activators led to the formation of aggregates composed of different cell types expressing adrenal progenitor or steroidogenic markers, including the adrenocortical specific enzyme Cyp21a1. Importantly, in vitro differentiated cells secreted the zona Fasciculata specific corticosterone in response to cAMP activators, but not gonadal hormones, thus confirming the specificity of differentiation towards the adrenal lineage. HighlightsO_LIMouse adrenal progenitors differentiate in a tenascin/fibronectin-rich extracellular matrix C_LIO_LIStepwise differentiation of ES cells yields NR5A1+ adrenocortical cells C_LIO_LI3D aggregates produce glucocorticoids in response to cAMP signalling C_LI

developmental biology↗

bioRxiv2023

MAFB drives differentiation by permitting WT1 binding to podocyte 1 specific promoters

Podocytes are highly specialized cells, but their chromatin status and the precise molecular events leading to their differentiation remain poorly defined. Here we used ChIP-Seq analysis for H3K4me3, H3K4me1 and H3K27me3 to establish the histone methylation map in adult mouse podocytes. Our data demonstrate open chromatin across podocyte specific genes and reveals that genes expressed in the mesoderm lineage become actively repressed upon podocyte differentiation. To better understand the transcriptional control of podocyte differentiation, we studied the role of transcription factor MAFB. ChIP-Seq experiments and functional analysis in conditional knockout mice identified a set of direct MAFB targets including Nphs1, Nphs2, Vegfa and Tcf21. Loss of MafB led to the deposition of extracellular matrix, progressive foot process effacement, and kidney disease. ChIP experiments in knockout animals revealed that during development MAFB is essential for H3K4me3 methylation and the recruitment of WT1 to the promoters of the podocyte specific genes Nphs1 and Nphs2. Taken together our data reveal the crucial function of MAFB by permitting chromatin accessibility at podocyte-specific genes during development and maintaining terminal differentiation in adults.

developmental biology↗

bioRxiv2020

Direct activation of RA signaling in cardiomyocytes protects hearts from apoptosis after myocardial infarction in mice

Retinoic acid (RA) is an essential signaling molecule for cardiac development and plays a protective role in the heart after myocardial infarction (MI). In both cases, the effect of RA signaling on cardiomyocytes, the principle cell type of the heart, has been reported to be indirect. Here we have developed an inducible murine transgenic RA-reporter line using CreERT2 technology that permits lineage tracing of RA-responsive cells and faithfully recapitulates endogenous RA activity in multiple organs during embryonic development. Strikingly, we have observed a direct RA response in cardiomyocytes during mid-late gestation and after MI. Ablation of RA signaling through deletion of the Aldh1a1/a2/a3 genes encoding RA-synthesizing enzymes leads to increased cardiomyocyte apoptosis in adults subjected to MI. RNA sequencing analysis reveals Tgm2 and Ace1, two genes with well-established links to cardiac repair, as potential targets of RA signaling in primary cardiomyocytes, thereby providing novel links between the RA pathway and heart disease.

developmental biology↗