Trans-differentiation of trophoblast stem cells: implications in placental biology

Abstract

Trophoblast invasion is a hallmark of hemochorial placentation. Invasive trophoblast cells replace the endothelial cells of uterine spiral arteries. The mechanism by which the invasive trophoblast cells acquire this phenotype is unknown. Here, we demonstrate that, during differentiation, a small population of trophoblast stem (TS) cells trans-differentiate into a hybrid cell type expressing markers of both trophoblast (TC) and endothelial (EC) cells. In addition, a compendium of EC-specific genes was found to be associated with TS cell differentiation. Using functional annotation, these genes were categorized into angiogenesis, cell adhesion molecules, and apoptosis-related genes. HES1 repressed transcription of EC genes in TS cells. Interestingly, differentiated TCs secrete TRAIL, but its receptor DR4 is expressed only in ECs and not in TCs. TRAIL induced apoptosis in EC but not in TC. Co-culture of ECs with TC induced apoptosis in ECs via extrinsic apoptotic pathway. These results highlight that (a) TS cells possess the potential to trans-differentiate into “trophendothelial” phenotype, regulated by HES1 and (b) trophoblast differentiation-induced TRAIL secretion directs preferential demise of ECs located in their vicinity.

Cellular Prion protein moonlights vascular smooth muscle cell fate: Surveilled by trophoblast cells

“…Trophoblast cellinduced de-differentiation leads to phenotypic switching in VSMCs that involve suppression of contractile markers expression and elevation of synthetic state markers (Nandy et al, 2020) Previous studies demonstrated that trophoblast cells isolated from first trimester human placenta expressed membrane-associated TRAIL and induced apoptosis of human aortic VSMC (Keogh et al, 2007). Expression of TRAIL in trans-differentiated trophendothelial cells was demonstrated by our laboratory (Paul et al, 2022).…”

“…Previous studies demonstrated that trophoblast cells isolated from first trimester human placenta expressed membrane‐associated TRAIL and induced apoptosis of human aortic VSMC (Keogh et al, 2007). Expression of TRAIL in trans‐differentiated trophendothelial cells was demonstrated by our laboratory (Paul et al, 2022). Our observation that RNA interference of PRNP in VSMCs caused apoptotic death led to our hypothesis that PRNP protects VSMCs from apoptotic cell death.…”

“…It was quite intriguing that PRNP formed a ter-molecular complex with PDGFRβ-FAK. VSMC de-differentiation is primarily directed by the invading interstitial trophoblast cells (Ain et al, 2003;Nandy et al, 2020) and trophendothelial cells (Paul et al, 2022). Trophoblast cellinduced de-differentiation leads to phenotypic switching in VSMCs that involve suppression of contractile markers expression and elevation of synthetic state markers (Nandy et al, 2020) Previous studies demonstrated that trophoblast cells isolated from first trimester human placenta expressed membrane-associated TRAIL and induced apoptosis of human aortic VSMC (Keogh et al, 2007).…”

“…Previous studies from our laboratory have shown that VSMCs surrounding the spiral arteries typically remain in a contractile state. VSMC de‐differentiation is primarily directed by the invading interstitial trophoblast cells (Ain et al, 2003; Nandy et al, 2020) and trophendothelial cells (Paul et al, 2022). Trophoblast cell‐induced de‐differentiation leads to phenotypic switching in VSMCs that involve suppression of contractile markers expression and elevation of synthetic state markers (Nandy et al, 2020).…”

“…Previous studies from our laboratory demonstrated that trophendothelial cells secrete TRAIL, which causes selective demise of endothelial cells but not trophoblast cells (Paul et al, 2022). We, therefore, tested whether PRNP has any role in TRAIL-induced apoptosis.…”