Functional Genomics Reveals a BMP-Driven Mesenchymal-to-Epithelial Transition in the Initiation of Somatic Cell Reprogramming

Abstract

Somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) by expression of defined embryonic factors. However, little is known of the molecular mechanisms underlying the reprogramming process. Here we explore somatic cell reprogramming by exploiting a secondary mouse embryonic fibroblast model that forms iPSCs with high efficiency upon inducible expression of Oct4, Klf4, c-Myc, and Sox2. Temporal analysis of gene expression revealed that reprogramming is a multistep process that is characterized by initiation, maturation, and stabilization phases. Functional analysis by systematic RNAi screening further uncovered a key role for BMP signaling and the induction of mesenchymal-to-epithelial transition (MET) during the initiation phase. We show that this is linked to BMP-dependent induction of miR-205 and the miR-200 family of microRNAs that are key regulators of MET. These studies thus define a multistep mechanism that incorporates a BMP-miRNA-MET axis during somatic cell reprogramming. PAPERCLIP:

Induction of pluripotency by defined factors

“…Moreover, the acceleration of MET promoted the reprogramming efficiency of mouse iPS cell induction. 72) It is known that TGF-O can induce the EMT at least partially through the activation of Snail. 73),74) TGF-O1 treatment or overexpression of Snail decreases the reprogramming efficiency.…”

“…BMP4 induces the expression of miRNA 205 and 200 families, which are key factors involved in the MET. 72) BMPs elicit important signals to maintain the pluripotency in mouse ES cells, together with leukemia inhibiting factor (LIF) signaling. 75) BMP2, BMP7 and BMP9 increase the reprogramming efficiency with OSKM.…”

“…75) BMP2, BMP7 and BMP9 increase the reprogramming efficiency with OSKM. 72) Conversely, the reprogramming efficiency was decreased by suppressing the BMP signaling using a BMP receptor antagonist, dorsomorphin, or a soluble BMP ligand antagonist, Noggin. This reduction of reprogramming efficiency was rescued by the overexpression of miRNA 200 family members.…”

“…This reduction of reprogramming efficiency was rescued by the overexpression of miRNA 200 family members. 72) The expression of epithelial genes was induced by the overexpression of Klf4, which bound the promoter of E-cadherin. KLF4 can be replaced by BMP4 to induce iPS cells.…”

Stem cell biology—from basic research to regenerative medicine

“…The review describes different methods to derive iPS cells as well as new discoveries about the molecular mechanisms that permit reprogramming to take place. Two processes that play a key role are the switch from mitochondrial-based oxidative phosphorylation to glycolysis that they recently discovered [5] and the way cells undergo a mesenchymal to epithelial transition [6]. The authors provide a comprehensive list of human diseases studied involving in vitro uses of iPSCs and their application in drug development and toxicology studies.…”