Persistent Human KIT Receptor Signaling Disposes Murine Placenta to Premature Differentiation Resulting in Severely Disrupted Placental Structure and Functionality

Abstract

Activating mutations in the human KIT receptor is known to drive severe hematopoietic disorders and tumor formation spanning various entities. The most common mutation is the substitution of aspartic acid at position 816 to valine (D816V), rendering the receptor constitutively active independent of ligand binding. As the role of the KIT receptor in placental signaling cascades is poorly understood, we analyzed the impact of KITD816V expression on placental development using a humanized mouse model. Placentas from KITD816V animals present with a grossly changed morphology, displaying a reduction in labyrinth and spongiotrophoblast layer and an increase in the Parietal Trophoblast Giant Cell (P-TGC) layer. Elevated differentiation to P-TGCs was accompanied with reduced differentiation to other Trophoblast Giant Cell (TGC) subtypes and by severe decrease in proliferation. The embryos display growth retardation and die in utero. KITD816V-trophoblast stem cells (TSC) differentiate much faster compared to wild type (WT) controls. In undifferentiated KITD816V-TSCs, levels of Phosphorylated Extracellular-signal Regulated Kinase (P-ERK) and Phosphorylated Protein Kinase B (P-AKT) are comparable to wildtype cultures differentiating for 3–6 days. Accordingly, P-TGC markers Placental Lactogen 1 (PL1) and Proliferin (PLF) are upregulated as well. The results reveal that KIT signaling orchestrates the fine-tuned differentiation of the placenta, with special emphasis on P-TGC differentiation. Appropriate control of KIT receptor action is therefore essential for placental development and nourishment of the embryo.

Choice of factors and medium impinge on success of ESC to TSC conversion

“…and Pcdh12 were downregulated in KIT D816V -TSCs in comparison to wildtype TSCs (Figure 46 C). These findings were also confirmed by in vivo analyses which demonstrated increased levels of P-TGC markers as well as decreased levels of S-TGC, C-TGC and SpA-TGC markers in KIT D816V -placentas (Kaiser et al, 2020b). Differentiation marker Hand1 which is expressed in the ectoplacental cone and mediates TGC differentiation was also significantly upregulated in KIT D816V -TSCs after six days of differentiation.…”

“…The placental structure was immensely affected -demonstrated by a decreased labyrinth and spongiotrophoblast layer. Further, an excessive and premature differentiation into P-TGC subtypes was detected while other TGCsubtypes remained underrepresented (Kaiser et al, 2020b). TGCs possess various functions essential for correct placental development.…”

“…Previously established data showed that the KIT D816V autoactivating mutation resulted in an aberrant placental phenotype characterized by reduced proliferation resulting in severe growth retardation of the embryo (Kaiser et al, 2020b). The placental structure was immensely affected -demonstrated by a decreased labyrinth and spongiotrophoblast layer.…”

Altered placental phenotype and increased risk of placental pathology in fetal spina bifida: a matched case-control study

“…Syncytiotrophoblast maturity scores were associated with global gene expression PC6 (β=0.01 [0.002, 0.02], p=0.02) and PC8 (β=0.01 [0.004, 0.02], p=0.008; Table 1). PC6 was characterized by genes involved in KIT receptor signaling, which regulates placental trophoblast invasion and differentiation (31, 32), and Interleukin-5 signaling, which promotes the proliferation and differentiation of various immune cells (33) (Table 2). PC8 was characterized by genes involved in RNA metabolism and processing (Table 2).…”

“…(β=0.01 [0.004, 0.02], p=0.008; Table1). PC6 was characterized by genes involved in KIT receptor signaling, which regulates placental trophoblast invasion and differentiation(31,32), and Interleukin-5 signaling, which promotes the proliferation and differentiation of various Eq. 1.Branchingmaturity score = ([terminal villi (%) + mature intermediate villi (%)] / [immature intermediate villi (%) + 1]) /100 Eq.…”