Cell stem cell最新文献

Midena et al.¹ employ a nanoengineered 3D "nichoid" substrate that mechanically supports CD34⁺ hematopoietic stem and progenitor cells (HSPCs) during ex vivo manipulation, reducing culture-associated stress and improving engraftment and polyclonal output after gene editing or lentiviral gene addition. The work spotlights mechanobiology as a manufacturing lever for improving HSPC gene therapies.

Clinical success of in vitro maturation (IVM) for fertility treatment is currently limited by the lack of a reliable source of ovarian support cells (OSCs) to nurture oocytes. Kramme et al. develop "Fertilo," a scalable, clinical-grade hiPSC-derived OSC product that significantly enhances oocyte maturation and improves clinical reproductive outcomes.¹.

Sleep disturbances are associated with pathogenesis of numerous chronic disorders, including chronic gastrointestinal diseases. However, the mechanism that transmits sleep disturbance-induced aberrant neural signaling from the brain to the gut remains elusive. We show that acute sleep deprivation (SD) impairs intestinal stem cell (ISC) function, leading to shortening of crypt-villus architecture and Paneth cell loss. We identified the dorsal motor nucleus of vagus (DMV) as the SD-sensitive central nervous system center that transmits sleep effects to the gut. SD aberrantly activates DMV neurons, driving excessive acetylcholine release from the vagus nerve into the gut. Acetylcholine triggers 5-hydroxytryptamine (5-HT) release by enterochromaffin cells and suppresses its reuptake via muscarinic receptors, thereby causing a spike in 5-HT levels. Elevated 5-HT induces excessive oxidative stress in ISCs through its receptor HTR4, promoting gut pathologies. Overall, we reveal an SD-responsive neural circuit that controls ISCs and identify therapeutic strategies for mitigating SD-related gut diseases.

In this issue, Apaydin and Sadhnani et al. report in situ genome editing of human skin to correct a common disease-causing mutation underlying autosomal recessive congenital ichthyosis (ARCI).¹ They combine a base editor, transient barrier modulation, and topical mRNA-lipid nanoparticle administration to restore clinically meaningful levels of transglutaminase 1 activity.

Allogeneic T cell therapies are a highly desirable option to circumvent the cost and complexity of using autologous T cells to treat diseases. Allogeneic CD8⁺ T cells can be made from pluripotent stem cells (PSCs), but deriving CD4⁺ T cells from PSCs has remained a significant challenge. Using feeder- and serum-free conditions, we found that CD4⁺ vs. CD8⁺ T cell commitment from PSCs can be controlled by fine-tuning the dynamics of Notch and T cell receptor (TCR) signaling delivered to CD4⁺CD8⁺ double-positive T cells. Notch signaling negatively impacts CD4⁺ T cell commitment, and its timed removal allows generation of clonally diverse and expandable CD4⁺ T cells from PSCs. The resulting CD4⁺ T cells respond to cytokine-mediated polarization by differentiating into Th1, Th2, or Th17 cells, recapitulating canonical helper cell function. These findings represent a significant step toward using PSC-derived CD4⁺ T cells as a low-cost, off-the-shelf cell therapy.

The pineal gland regulates circadian rhythms through melatonin production, yet human studies are limited by poor tissue access. To overcome this, we developed human pineal gland organoids (hPGOs) from pluripotent stem cells, modeling pineal development and function. Single-cell RNA sequencing revealed distinct mature and developing pinealocyte populations with transcriptomic profiles closely resembling the in vivo pineal gland. hPGOs produce melatonin, express adrenergic receptors, and respond to noradrenaline, mimicking physiological regulation. To model disease-related impairments, we generated hPGOs from Angelman syndrome (AS) patient-derived iPSCs, which exhibit disrupted pinealocyte differentiation and markedly reduced melatonin synthesis, reflecting AS-related developmental pathology. Additionally, transplanted hPGOs restored circulating melatonin in pinealectomized mice, demonstrating their potential for cell-therapy approaches. These findings establish hPGOs as a robust platform for probing pineal development, circadian regulation, and their disruption in neurodevelopmental and sleep-related disorders.

Short bowel syndrome (SBS) is a life-threatening condition in which outcomes often critically depend on ileal function, the only intestinal segment specialized for bile acid uptake and efficient fat absorption. However, whether restoring ileal epithelium-specific nutrient absorption can ameliorate SBS has remained unknown. Here, we demonstrate a niche-preserving transplantation strategy enabling highly efficient engraftment of intestinal organoids into the rat small intestine. Clearing luminal mucus with N-acetylcysteine facilitates ethylenediaminetetraacetic acid (EDTA)-based epithelial detachment, enabling removal of Lgr5⁺ stem cells while preserving the stromal niche. This preconditioning increased the engrafted area and enabled the generation of an ilealized jejunum that improved body-weight trajectories and survival in rat SBS. Furthermore, the engrafted epithelia endowed the jejunum with bile acid absorption capacity. These findings provide in vivo evidence for stem cell niche theory, showing that the niche is essential to accommodate donor stem cells, and establish ilealized jejunum as a path toward autologous, region-targeted therapy for SBS.

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS), resulting in neurological disability that worsens over time. While progress has been made in defining the immune system's role in MS pathophysiology, the contribution of intrinsic CNS cell dysfunction remains unclear. Here, we generated a collection of induced pluripotent stem cell (iPSC) lines from people with MS spanning diverse clinical subtypes and differentiated them into glia-enriched cultures. Using single-cell transcriptomic profiling and orthogonal analyses, we observed several distinguishing characteristics of MS cultures pointing to glia-intrinsic disease mechanisms. We found that primary progressive MS-derived cultures contained fewer oligodendrocytes. Moreover, MS-derived oligodendrocyte lineage cells and astrocytes showed increased expression of immune and inflammatory genes, matching those of glia from MS postmortem brains. Thus, iPSC-derived MS models provide a unique platform for dissecting glial contributions to disease phenotypes independent of the peripheral immune system and identify potential glia-specific targets for therapeutic intervention.

Regeneration is a heroic biological process that restores tissue architecture and function in the face of day-to-day cell loss or the aftershock of injury. Capacities and mechanisms for regeneration can vary widely among species, organs, and injury contexts. Here, we describe "hallmarks" of regeneration found in diverse settings of the animal kingdom, including activation of a cell source, initiation of regenerative programs in the source, interplay with supporting cell types, and control of tissue size and function. We discuss these hallmarks with an eye toward major challenges and applications of regenerative biology.