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The human placenta, a unique tumor-like organ, is thought to exhibit rare aneuploidy associated with adverse pregnancy outcomes. Discrepancies in reported aneuploidy prevalence in placentas stem from limitations in modeling and detection methods. Here, we use isogenic trophoblast stem cells (TSCs) derived from both naïve and primed human pluripotent stem cells (hPSCs) to reveal the spontaneous occurrence of aneuploidy, suggesting chromosomal instability (CIN) as an inherent feature of the trophoblast lineage. We identify potential pathways contributing to the occurrence and tolerance of CIN, such as autophagy, which may support the survival of aneuploid cells. Despite extensive chromosomal abnormalities, TSCs maintain their proliferative and differentiation capacities. These findings are further validated in placentas, where we observe a high prevalence of heterogeneous aneuploidy across trophoblasts, particularly in invasive extravillous trophoblasts. Our study challenges the traditional view of aneuploidy in the placenta and provides insights into the implications of CIN in placental function. Studies have shown that placental aneuploidy is correlated with adverse pregnancy outcomes, though few causative data are available. Here they show that chromosomal instability is an inherent feature of trophoblasts and normal human placentas, without functional compromise, and provide mechanisms for how this damage is tolerated.

Neuronal conversion from human fibroblasts can be induced by lineage-specific transcription factors; however, the introduction of ectopic genes limits the therapeutic applications of such induced neurons (iNs). Here, we report that human fibroblasts can be directly converted into neuronal cells by a chemical cocktail of seven small molecules, bypassing a neural progenitor stage. These human chemical-induced neuronal cells (hciNs) resembled hiPSC-derived neurons and human iNs (hiNs) with respect to morphology, gene expression profiles, and electrophysiological properties. This approach was further applied to generate hciNs from familial Alzheimer's disease patients. Taken together, our transgene-free and chemical-only approach for direct reprogramming of human fibroblasts into neurons provides an alternative strategy for modeling neurological diseases and for regenerative medicine.

Proplatelet formation is a part of the intricate process by which platelets are generated by their precursor cell, the megakaryocyte. The processes that drive megakaryocyte maturation and platelet production are however still not well understood. The protein kinase C (PKC) family of serine/threonine kinases has been demonstrated as an important regulator of megakaryocyte maturation and proplatelet formation, but little investigation has been made on the individual isoforms. We have previously shown, in mouse models, that PKCα plays a vital role in regulating platelet function, so in this study we aimed to investigate the role of PKCα in megakaryocyte function using the same Prkca(-)(/)(-) mice. We assessed the role of global PKC and specifically PKCα in proplatelet formation in vitro, analyzed polyploidy in Prkca(-)(/)(-)-derived megakaryocytes and followed platelet recovery in platelet-depleted Prkca(-)(/)(-) mice. We show reduced proplatelet formation in the presence of global PKC blockade. However, in the presence of a selective classical PKC isoform inhibitor, Go6976, proplatelet formation was conversely enhanced. PKCα null megakaryocytes also showed enhanced proplatelet formation, as well as a shift to greater polyploidy. In vivo, platelet production was enhanced in response to experimentally induced immune thrombocytopenia. In conclusion, our data indicate that classical PKC isoforms, and more specifically PKCα, are negative regulators of proplatelet formation. PKCα appears to negatively regulate endomitosis, with the enhanced polyploidy observed in Prkca(-)(/)(-)-derived megakaryocytes. In vivo, these observations may culminate in the observed ability of Prkca(-)(/)(-) mice to recover more rapidly from a thrombocytopenic insult.