Farzad Fattah

Adult hematopoietic stem cells (HSCs) and bone marrow (BM) mesenchymal stem/stromal cells (MSCs) are essential for lifelong hematopoiesis, skeletal homeostasis, immune competence, and tissue regeneration. The use of electronic cigarettes (E-cigs) among women of reproductive age continues to rise, raising concerns about potential adverse developmental effects; however, the long-term consequences of maternal E-cig vaping on offspring BM stem cell function and hematopoietic homeostasis remain incompletely understood. Here, using a rat model of maternal E-cig exposure (containing nicotine) during gestation, combined with longitudinal in vivo analyses and complementary ex vivo studies of human cells, we show that prenatal E-cig exposure is associated with persistent alterations in offspring BM stem cell function and lineage commitment. Gestational E-cig exposure was associated with expansion of the CD11b/c⁺ myeloid-enriched compartment, increased CD90⁺ stromal cells, and impaired osteogenic differentiation in rat offspring. Complementary experiments using primary human cells showed that nicotine exposure was associated with reduced T-cell proliferation and impaired cytotoxic activity in a proof-of-principle co-culture assay. Mechanistically, transcriptomic profiling followed by Gene Ontology and pathway enrichment analyses identified alterations in molecular programs associated with KLF4–Notch1 signaling, mitochondrial biogenesis, inflammation, and stem cell regulation in the BM of E-cig-exposed rat offspring. Changes in CCL11, FTO, and RUNX2 were additionally associated with an inflammatory and aging-related molecular phenotype that persisted from early life into adulthood, although these findings do not establish a causal CCL11–FTO–RUNX2 signaling axis or direct cellular senescence. Collectively, our study provides a phenotypic and mechanistic framework for understanding how maternal E-cig exposure may influence long-term offspring hematopoietic, skeletal, and immune health while highlighting the need for further studies to establish causal molecular mechanisms and determine their relevance to maternal E-cig use in humans.

Periodontitis, a chronic inflammatory disease caused by bacterial infections in dental plaque, results in an environment rich in oxidative stress and pro-inflammatory cytokines, both of which contribute to oral cancers development. One critical mediator of inflammation in periodontitis is pyroptosis, a form of programmed cell death linked to inflammatory processes. Gasdermin D (GSDMD) is a key player in pyroptosis, where its cleavage forms membrane pores, leading to cell rupture and the release of pro-inflammatory cytokines like IL-1β and IL-18 creating an environment that favors cancer cell survival and proliferation. In periodontitis, pyroptosis is closely associated with the activation of inflammasomes, particularly NLRP3, in response to oral bacteria, which in turn leads to the release of cytokines that exacerbate inflammation. Furthermore, the tissue breakdown caused by pyroptosis releases damage-associated molecular patterns (DAMPs), which can activate oncogenic signaling in neighboring epithelial cells, further promoting oral cancers development. So, inhibiting pyroptotic mediators like GSDMD or NLRP3 inflammasomes can reduce inflammation in periodontitis and slow oral cancer progression. Interestingly, inducing pyroptosis in cancer cells or infected tissues may offer a potential therapeutic approach. These findings underscore the critical link between periodontitis, pyroptosis, and oral cancer, suggesting that targeting these pathways may offer therapeutic potential for preventing or treating both diseases. This review aims to elucidate the role of pyroptosis in periodontitis, their impacts on oral cancers, and the potential therapeutic strategies to modulate this inflammatory cell death.