Bioessays

Kostic, Lana; Barker, Nick

doi: 10.1002/bies.70044pmid: 40697061

The localization and identity of esophageal stem cells remain highly debated, prompting the emergence of several hypotheses. Although early models proposed a homogeneous basal progenitor layer, recent evidence suggests a heterogeneous pool of stem/progenitor cells with diverse phenotypic and functional characteristics. We present a perspective on this heterogeneity and its implications for both normal tissue maintenance and disease susceptibility. Esophageal cancers can emerge as a result of random mutations or the activity of cancer stem cells (CSCs). The multifaceted interactions between genetic predisposition and environmental influences demonstrate that cancer onset can be driven not only by cell phenotype but also by various external pressures. Advances in in vivo and in vitro models now offer valuable tools to explore these stem cell dynamics and may pave the way for novel therapeutic approaches in esophageal cancer treatment.

Fujino, Hiromichi

doi: 10.1002/bies.70046pmid: 40697058

In this article, onset mechanisms of colorectal cancer and intestinal bowel diseases (IBD) are postulated to involve the aberrant expression/hyper‐activation of E‐type prostanoid 4 (EP4) receptors. Although prostaglandin E2 and EP4 receptors are important factors for maintaining colorectal homeostasis, their mediated signaling is also considered to be involved in the etiology of severe intestinal diseases. To prevent uncontrollable activations of EP4 receptors, two safety factors are proposed: butyrate as an external safety factor and interleukin (IL)‐4 as an internal safety factor. Thus, for maintaining vulnerable colorectal homeostasis, the levels of EP4 receptors, butyrate, and IL‐4 are proposed as an important triad for protecting against development/onset risks of, at least, EP4 receptor‐mediated cancer and IBD.

doi: 10.1002/bies.70052pmid: N/A

Pociūtė, Agnė; Pivoriūnas, Augustas

doi: 10.1002/bies.70040pmid: 40662277

Extracellular vesicles (EVs) are secreted by all types of cells in the central nervous system (CNS) and participate in intercellular communication in physiological and pathological settings. However, an emerging view of multidirectional communications is getting incredibly complex, and, in most cases, it is unclear whether EVs secreted by specific cell populations have specific cellular targets. Here we propose to discriminate between short‐ (adjacent cells) and long‐ (different brain regions) range signaling of the EVs in the CNS. We also hypothesize that besides its primary function of brain clearance, the glymphatic system can also serve for the long‐range transport and signaling of the EVs throughout the CNS. In the first part of the review, we will describe currently available experimental models used for labeling and tracking cell‐type specific EVs in the CNS. Then we will briefly overview the glymphatic system and discuss current evidence showing the physiological and pathological significance of long‐range EV signaling in the CNS. Finally, we will provide a hypothetical model describing the possible role of the glymphatic system in the transport and long‐range signaling of the EVs.

Brunetta, Henver S.; Mori, Marcelo A.; Bartelt, Alexander

doi: 10.1002/bies.70038pmid: 40619853

Mitochondrial membrane potential is highly dependent on coupled as well as uncoupled respiration. While brown adipose tissue (BAT) mediates non‐shivering thermogenesis (NST), a highly adaptive bioenergetic process critical for energy metabolism, the relationship of coupled and uncoupled respiration in thermogenic adipocytes remains complicated. Uncoupling protein 1 (UCP1)‐mediated proton leak is the primary driver of NST, but recent studies have shown that oxidative phosphorylation may be an underappreciated contributor to UCP1‐dependent NST. Here, we highlight the role of ATP synthase for BAT thermogenesis and discuss the implications of fine‐tuning adrenergic signaling in brown adipocytes by the protein inhibitory factor 1 (IF1). We conclude by hypothesizing future directions for mitochondrial research, such as investigating the potential role of IF1 for mitochondrial substrate preference, structural dynamics, as well as its role in cell fate decision and differentiation.

Mahawar, Usha; Wattenberg, Binks

doi: 10.1002/bies.70036pmid: 40548458

Sphingolipids are a structurally unique, widespread, and diverse family of lipids. Serine palmitoyltransferase (SPT) is the first and rate‐limiting enzyme required for the synthesis of all sphingolipids. Not unexpectedly, SPT is highly regulated. SPT is a multi‐subunit enzyme, the level of activity of which is controlled by the regulatory subunits known as the ORMDLs. Here, we discuss how the regulation of SPT activity is accomplished by multiple mechanisms, underscoring the importance of this regulation. A rapid homeostatic regulation of SPT, monitoring cellular sphingolipid levels, is mediated by the direct binding of the central sphingolipid ceramide to the SPT/ORMDL complex. This acute regulation is overlaid by a longer‐term regulation in which ORMDL is removed from the remainder of the SPT complex and trafficked for degradation, resulting in enhanced SPT activity. A third level of regulation is conferred by the inclusion of specific isoforms of the subunits of SPT into the complex. The isoform composition of the SPT complex dictates both the sensitivity of the complex to levels of cellular sphingolipid and the molecular species of sphingoid backbone that are produced. Here we discuss the mechanisms, interplay, and physiological roles of these three levels of regulation of sphingolipid biosynthesis.

Morizet, David; Bally‐Cuif, Laure

doi: 10.1002/bies.70041pmid: 40658885

The reduction of adult neurogenesis in the human brain, compared to other vertebrate species, has been proposed to result from an active counter‐selection to permit the stability of circuits needed for long‐term memorization and higher cognitive abilities. Here, bringing forward behavior studies and evolution‐based observations, we discuss the benefits of adult neurogenesis and data suggesting that its loss is unlinked with cognitive levels. Considering cell lineages and functional assays, we further note that human‐specific genomic features (such as novel gene variants or regulatory sequences) frequently hit pathways that may lead to the premature exhaustion of embryonic neural progenitors after the developmental phase of cortex formation. We propose that reduced adult neurogenesis in humans may be a tradeoff for these changes, themselves selected for to permit the enlargement and complexification of the cerebral cortex during development.

Speijer, Dave

doi: 10.1002/bies.70045pmid: 40697051

Recently, a fascinating, well‐executed, molecular study regarding the direct influence of mitochondrial reactive oxygen species (ROS) formation by the electron transport chain (ETC) on mitochondrial morphology in baker's yeast appeared in PNAS. The findings highlight some very interesting connections between the choice of metabolic substrates, points of entry into the ETC, ROS formation, efficiency of ATP generation, and mitochondrial structures. These reflect both ancient eukaryotic constraints and later specific adaptations of Saccharomyces cerevisiae. However, by not addressing these adaptations, the important wider implications of the article's findings run the risk of being overlooked. There are illuminating connections to the FADH2/NADH ratio concept and new studies replacing ETC components with yeast counterparts in diverse metazoan cells, which will also be discussed.

Chakraborty, Chaitali; Nissen, Itzel; Remeseiro, Silvia

doi: 10.1002/bies.70043pmid: 40685688

Neuron–glioma interactions are critical drivers of glioma progression, with neuronal activity promoting tumor growth and invasion through paracrine signaling and direct synaptic input. Beyond well‐established glutamatergic synapses, recent discoveries revealed that GABAergic interactions also contribute to glioma proliferation. Here, we focus on how glioma cells decode neuronal cues via epigenetic mechanisms, including enhancer reprogramming, chromatin remodeling, and rewiring of 3D genome organization, with transcriptions factors such as SMAD3 and PITX1 orchestrating transcriptional programs that sustain neuron‐to‐glioma communication. Additionally, recent integration of multi‐omics data highlights gene regulatory networks linked to GABAergic signaling as contributors to glioblastoma (GB) pathogenesis. We also underscore the distinct roles of GABAergic signaling across glioma subtypes, noting that, in GB, GABA‐related metabolic and paracrine mechanisms, rather than synaptic input, may drive tumor progression. Understanding how epigenetic reprogramming facilitates glioma integration into neural circuits opens new avenues to disrupt these malignant neuron–glioma interactions by targeting the epigenetic machinery.