Cell Stem Cell

A 3D “nichoid” boost for gene-engineered blood stem cells Midena et al. 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.

A 3D “nichoid” boost for gene-engineered blood stem cells

Editing the skin in place: In vivo genome correction of rare skin disease 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). They combine a base editor, transient barrier modulation, and topical mRNA-lipid nanoparticle administration to restore clinically meaningful levels of transglutaminase 1 activity.

Editing the skin in place: In vivo genome correction of rare skin disease

Nurturing eggs with hiPSC-derived cells to improve outcomes in in vitro fertilization 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.

Nurturing eggs with hiPSC-derived cells to improve outcomes in in vitro fertilization

Sleep disturbance triggers aberrant activation of vagus circuitry and induces intestinal stem cell dysfunction Yu and colleagues uncover a sleep disturbance-responsive neuroendocrine pathway that, when hyperactivated, induces 5-hydroxytryptamine (5-HT) receptor-dependent oxidative stress in intestinal stem cells and drives gut pathologies. Targeting the dorsal motor nucleus of vagus-vagus nerve-5-HT axis offers therapeutic opportunities for sleep disturbance-associated gastrointestinal disorders.

Sleep disturbance triggers aberrant activation of vagus circuitry and induces intestinal stem cell dysfunction

Lipid nanoparticle-based non-viral in situ gene editing of congenital ichthyosis-causing mutations in human skin models Hedtrich and colleagues developed a topical, laser-assisted LNP approach to deliver gene editors into human skin. Their method corrects a disease-causing TGM1 mutation in ARCI models, restores TG1 function, and shows excellent safety, highlighting a minimally invasive strategy for treating severe genetic skin disorders.

Lipid nanoparticle-based non-viral in situ gene editing of congenital ichthyosis-causing mutations in human skin models

High-content screening of organoids reveals the mechanisms of human pancreas acinar specification Keshara et al. conducted a high-content screen on pancreas organoids that identified 54 compounds affecting differentiation or morphogenesis. After validating 11 compounds, they focus on Gsk3A/B inhibitors, which, combined with FGF withdrawal, drive acinar cell differentiation, enabling future studies on these cells and their role in cancer initiation in humans.

High-content screening of organoids reveals the mechanisms of human pancreas acinar specification

Challenges and opportunities for human Organ Chips in FDA assessments and pharma pipelines This perspective article by Don Ingber reviews the challenges and opportunities relating to the Food and Drug Administration's recently announced plan to phase out animal-testing requirements for drug assessments based on advances in new approach methodologies, with a focus on human organ-on-a-chip technology.

Challenges and opportunities for human Organ Chips in FDA assessments and pharma pipelines

Development of human induced pluripotent stem cell-derived ovarian support cells as a clinical-grade product for in vitro fertilization Paulsen et al. present the process development and clinical application of an hiPSC-derived OSC product, Fertilo. They describe the raw material upgrades, process consistency and reproducibility, and analytical assessment required for the generation of a clinically suitable product, as well as favorable outcomes from the first-in-human application of Fertilo.

Development of human induced pluripotent stem cell-derived ovarian support cells as a clinical-grade product for in vitro fertilization

Activation of a branched-chain amino acid rheostat restores replication-dependent hematopoietic stem cell fitness Bartram et al. show that HSCs with accrued divisions generate low-output progeny that are highly variable in lineage distribution and transcriptionally divergent within individual lineages. HSC functional decline arises from redirecting BCAA usage from catabolic toward anabolic activity. BCAA metabolite replacement restores division-dependent HSC fitness.

Activation of a branched-chain amino acid rheostat restores replication-dependent hematopoietic stem cell fitness

Nanoengineered extrusion-aligned tract bioprinting enables functional repair of spinal cord injuries Gu et al. present NEAT, a nanoengineered extrusion-aligned tract bioprinting strategy that fabricates aligned, human neural stem cell-laden collagen hydrogel constructs through shear-induced fibrillar organization. In a rat model of complete spinal cord transection, NEAT enables axonal reconnection and functional locomotor recovery, demonstrating its translational potential for spinal cord repair and neural tissue engineering.

Nanoengineered extrusion-aligned tract bioprinting enables functional repair of spinal cord injuries

Retinal ganglion cell survival and functional maturation in transiently vascularized human retinal organoids Sharma et al. present a bioengineered retinal organoid system that supports long-term survival and functional maturation of retinal ganglion cells through transient vascular support and microfluidic guidance. The platform sustains neuronal activity and enables circuit-level light responses in advanced human retinal models.

Retinal ganglion cell survival and functional maturation in transiently vascularized human retinal organoids

Human pluripotent stem cell-derived innate and adaptive immune cells for cancer immunotherapy Human pluripotent stem cells offer a scalable platform for generating immune effector cells with enhanced anti-tumor potential. This review explores recent advances in hPSC-derived NK cells, T cells, and macrophages, highlighting strategies to overcome immunogenicity, toxicity, and scalability challenges in allogeneic cancer immunotherapy.

Human pluripotent stem cell-derived innate and adaptive immune cells for cancer immunotherapy

Nanoengineered 3D culture substrate enables superior persistence and polyclonal engraftment of genetically engineered hematopoietic stem cells Preserving the functionality of hematopoietic stem cells during ex vivo manipulation for clinical applications remains a challenge. Here, Midena et al. implement a nanoengineered 3D culture substrate compatible with multiple gene therapy platforms that enhances the engraftment and clonal output of engineered cells through biomechanical regulation of stem cell properties.

Nanoengineered 3D culture substrate enables superior persistence and polyclonal engraftment of genetically engineered hematopoietic stem cells

A peripheral glial niche orchestrates the early stages of skin wound healing Repair glia in peripheral nerves are part of a regenerative niche in acute skin wounds. This glial niche promotes skin wound healing by regulating innate immune cell recruitment, in particular monocytes and monocyte-derived macrophages, both critical for a successful repair process.

A peripheral glial niche orchestrates the early stages of skin wound healing

Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration (Cell Stem Cell 31, 1162–1174.e1–e9; August 1, 2024)

Genome-wide CRISPR screen identifies neddylation as a regulator of neuronal aging and AD neurodegeneration

Chromatin Accessibility Dynamics during Chemical Induction of Pluripotency (Cell Stem Cell 22, 529–542.e1–e5; April 5, 2018)

Online Now! Chromatin Accessibility Dynamics during Chemical Induction of Pluripotency #stemcells

Lipid nanoparticle-based non-viral in situ gene editing of congenital ichthyosis-causing mutations in human skin models Hedtrich and colleagues developed a topical, laser-assisted LNP approach to deliver gene editors into human skin. Their method corrects a disease-causing TGM1 mutation in ARCI models, restores TG1 function, and shows excellent safety, highlighting a minimally invasive strategy for treating severe genetic skin disorders.

Online Now! Lipid nanoparticle-based non-viral in situ gene editing of congenital ichthyosis-causing mutations in human skin models #stemcells

High-content screening of organoids reveals the mechanisms of human pancreas acinar specification Keshara et al. conducted a high-content screen on pancreas organoids that identified 54 compounds affecting differentiation or morphogenesis. After validating 11 compounds, they focus on Gsk3A/B inhibitors, which, combined with FGF withdrawal, drive acinar cell differentiation, enabling future studies on these cells and their role in cancer initiation in humans.

Online Now! High-content screening of organoids reveals the mechanisms of human pancreas acinar specification #stemcells

Challenges and opportunities for human Organ Chips in FDA assessments and pharma pipelines, This perspective article by Don Ingber reviews the challenges and opportunities relating to the Food and Drug Administration's recently announced plan to phase out animal-testing requirements for drug assessments based on advances in new approach methodologies, with a focus on human organ-on-a-chip technology.

Online Now! Challenges and opportunities for human Organ Chips in FDA assessments and pharma pipelines, #stemcells

Nanoengineered extrusion-aligned tract bioprinting enables functional repair of spinal cord injuries Gu et al. present NEAT, a nanoengineered extrusion-aligned tract bioprinting strategy that fabricates aligned, human neural stem cell-laden collagen hydrogel constructs through shear-induced fibrillar organization. In a rat model of complete spinal cord transection, NEAT enables axonal reconnection and functional locomotor recovery, demonstrating its translational potential for spinal cord repair and neural tissue engineering.

Online Now! Nanoengineered extrusion-aligned tract bioprinting enables functional repair of spinal cord injuries #stemcells

Development of human induced pluripotent stem cell-derived ovarian support cells as a clinical-grade product for in vitro fertilization Paulsen et al. present the process development and clinical application of an hiPSC-derived OSC product, Fertilo. They describe the raw material upgrades, process consistency and reproducibility, and analytical assessment required for the generation of a clinically suitable product, as well as favorable outcomes from the first-in-human application of Fertilo.

Online Now! Development of human induced pluripotent stem cell-derived ovarian support cells as a clinical-grade product for in vitro fertilization #stemcells

Activation of a branched-chain amino acid rheostat restores replication-dependent hematopoietic stem cell fitness Bartram et al. show that HSCs with accrued divisions generate low-output progeny that are highly variable in lineage distribution and transcriptionally divergent within individual lineages. HSC functional decline arises from redirecting BCAA usage from catabolic toward anabolic activity. BCAA metabolite replacement restores division-dependent HSC fitness.

Online Now! Activation of a branched-chain amino acid rheostat restores replication-dependent hematopoietic stem cell fitness #stemcells

Retinal ganglion cell survival and functional maturation in transiently vascularized human retinal organoids Sharma et al. present a bioengineered retinal organoid system that supports long-term survival and functional maturation of retinal ganglion cells through transient vascular support and microfluidic guidance. The platform sustains neuronal activity and enables circuit-level light responses in advanced human retinal models.

Online Now! Retinal ganglion cell survival and functional maturation in transiently vascularized human retinal organoids #stemcells

Reverse engineering the beat: Assembloid modeling of sympathetic control of the heart Liu et al. generate human sympathetic ganglion organoids and assemble them with heart-forming organoids to build functionally connected sympathetic-cardiac organoids in vitro. Their platform captures autonomic development, neuromodulation of heart function, and metabolic injury, opening new opportunities to study human autonomic disorders and cardiometabolic disease.

Reverse engineering the beat: Assembloid modeling of sympathetic control of the heart

Pineal gland organoids illuminate human melatonin and circadian regulation Human pineal development and neuroendocrine regulation remain incompletely understood at the molecular and functional levels. Kiral et al. establish human pineal gland organoids (hPGOs) that recapitulate pinealocyte maturation, noradrenergic responsiveness, and melatonin synthesis, providing a platform for investigating circadian dysfunction and disease-associated sleep disturbances.

Pineal gland organoids illuminate human melatonin and circadian regulation

Two isoforms, two outcomes: How NTRK2 shapes vascular regeneration In this issue of Cell Stem Cell, Zhang et al. identify a pathological NTRK2 isoform switch in bronchopulmonary dysplasia that alters the regenerative capacity of capillary endothelial cells, highlighting isoform-specific targeting as a promising strategy for vascular repair.

Two isoforms, two outcomes: How NTRK2 shapes vascular regeneration

A sculptor of modern regenerative medicine Editors’ note: The Ogawa-Yamanaka Stem Cell Prize recognizes groundbreaking work in translational regenerative medicine using reprogrammed cells. The prize is supported by Gladstone Institutes, in partnership with Cell Press. Among his myriad accomplishments, Rudolf Jaenisch—winner of the 2025 Ogawa-Yamanaka Stem Cell Prize—was the first to demonstrate the potential of induced pluripotent stem cells to treat disease.

A sculptor of modern regenerative medicine

Anti-aging strategies and ex vivo organ rejuvenation This perspective highlights anti-aging strategies with an emphasis on the partial reprogramming approach for cellular rejuvenation and extending healthspan. It also discusses the use of ex vivo perfusion technology to help bring innovative therapies, like partial reprogramming, into clinical practice.

Anti-aging strategies and ex vivo organ rejuvenation

Transcriptional code for circuit integration in the injured brain by transplanted human neurons Wang et al. show that grafted cortical neurons reconstitute the ischemic cortex while extending specific projections and forming functional synapses with host neurons in the brain and spinal cord. Projections are segregated by transcriptional subtypes, revealing intrinsic transcriptional programs that encode projection preferences and enable subtype-specific circuit integration during repair.

Transcriptional code for circuit integration in the injured brain by transplanted human neurons

Tunable differentiation of human CD4+ and CD8+ T cells from pluripotent stem cells Jones et al. demonstrate that Notch signaling suppresses CD4+ (helper) T cell induction from PSCs and that manipulating TCR and Notch signaling enables control over CD4+ vs. CD8+ (cytotoxic) T cell production. The resulting PSC-CD4+ T cells achieve a naive/memory phenotype and are capable of functional Th1/2/17 polarization.

Tunable differentiation of human CD4+ and CD8+ T cells from pluripotent stem cells