Cell Stem Cell

Neuronal VIP shapes intestinal stem cell activity and mucosal immunity Intestinal homeostasis and regeneration rely on intestinal stem cells (ISCs). Li et al. identified neuronal vasoactive intestinal peptide (VIP) as a brake on ISCs through VIPR1 to limit regeneration. In Nature Immunology, Jakob et al. and Pirzgalska et al. further showed that VIP-VIPR1 signaling restrains secretory lineage expansion and balances immune responses.

Neuronal VIP shapes intestinal stem cell activity and mucosal immunity

Cradles for maturation: Turning progenitor cells into functional intestinal epithelium Maimets et al. reveal that appropriate tissue shape is required during maturation of the intestinal epithelium from the fetal to adult state, and this transition is mediated by the mechanotransduction protein—YAP. The introduced method transforms fetal cells into mature, functional cells in vitro, unachievable by traditional three-dimensional cultures.

Cradles for maturation: Turning progenitor cells into functional intestinal epithelium

Off-the-shelf CAR natural killer progenitor cell therapies are built to last Induced pluripotent stem cell (iPSC)-derived chimeric antigen receptor (CAR) natural killer (NK) cells are an emerging class of off-the-shelf cellular immunotherapy limited by short-term persistence. Wang et al. develop a platform for lineage-committed progenitor cell therapy to sustain in vivo CAR iNK cell lymphopoiesis and enhance tumor control.

Off-the-shelf CAR natural killer progenitor cell therapies are built to last

Tissues assemble! Rebuilding the human periportal liver in a dish In their recent Nature paper, Yuan et al. reconstruct patient-specific periportal architecture by assembling hepatocyte organoids with cholangiocytes and portal mesenchyme. Unlike previous attempts, these multicellular units recapitulate much of the cell-cell interaction found in the adult human liver, providing a new sophisticated platform to understand liver biology.

Tissues assemble! Rebuilding the human periportal liver in a dish

Two decades of induced pluripotent stem cell research: From discovery to diverse applications Since the discovery of induced pluripotent stem cells (iPSCs) 20 years ago, iPSC technology has transformed stem cell research and regenerative medicine. This perspective reviews key advances in reprogramming mechanisms and highlights the growing clinical, translational, and societal applications of iPSCs.

Two decades of induced pluripotent stem cell research: From discovery to diverse applications

Adult neurogenesis: New neurons, new opportunities Kempermann and colleagues discuss new directions in neuroscience stemming from an understanding that adult neurogenesis contributes to brain function in health and disease. They discuss the role and function of adult stem cells; the impact of environmental regulation; the interplay between development, plasticity, and aging; and other fundamental questions.

Adult neurogenesis: New neurons, new opportunities

Modeling human prenatal adrenocortical functional zonation dynamics from pluripotent stem cells Mayama and colleagues generate ACTH-responsive, cortisol- and androgen-producing human adrenocortical cells from induced pluripotent stem cells. This platform models prenatal functional zonation in vitro and in vivo, enabling mechanistic studies of human adrenal development and steroidogenesis and providing a foundation for future cell-based therapies for adrenal disorders.

Modeling human prenatal adrenocortical functional zonation dynamics from pluripotent stem cells

Randomized phase 2b dose-escalation trial of stem cell therapy with laromestrocel for aging frailty Ruiz et al. present results of a phase 2 randomized trial of intravenous laromestrocel, a mesenchymal stem cell product, which improved the physical condition of patients with age-related clinical frailty after 9 months, compared with placebo. Reduced sTIE2 in blood provides a mechanistic link to improved vascular function and inflammaging.

Randomized phase 2b dose-escalation trial of stem cell therapy with laromestrocel for aging frailty

Pluripotent stem cell-derived CAR-NK progenitor therapy targets minimal residual disease and prevents relapse in leukemia models NK cell therapy lacks sustained efficacy in treating tumors. Wang and colleagues developed a pluripotent stem cell-derived induced NK lineage-committed progenitor (iNKP) cell therapy, which showed persisting iNK cells in vivo and reduced cancer relapse by eradicating MRD.

Pluripotent stem cell-derived CAR-NK progenitor therapy targets minimal residual disease and prevents relapse in leukemia models

Minimizing far-extending chromatin perturbation in genome editing preserves stem cell identity Zhu et al. report that CRISPR editing displaces CTCF- and condensate-associated distal regulations, rewiring 3D genomic regulation. Even distal cleavage causes stem cell differentiation. The authors propose strategies to minimize chromatin disruption and preserve cell identity.

Minimizing far-extending chromatin perturbation in genome editing preserves stem cell identity

comBO: A combined human bone and lympho-myeloid bone marrow organoid for preclinical modeling of hematopoietic disorders Shen et al. report comBO, a combined human bone and bone marrow model that integrates osteolineage, vascular, stromal, and hematopoietic compartments in a single hiPSC-derived organoid system. comBO supports primary patient cells for preclinical disease modeling, identifying and validating MIF as a targetable inflammatory axis in myeloma-comBO chimeroids.

comBO: A combined human bone and lympho-myeloid bone marrow organoid for preclinical modeling of hematopoietic disorders

Distinct spatial patterning and transcriptomic landscapes of human neural organoids by localized delivery of morphogens Kim and colleagues developed a passive diffusion morphogen gradient generator that establishes a steep exogenous spatial gradient for organoid patterning. This approach creates distinct dorsal-ventral or rostral-caudal patterns within individual organoids. Spatial transcriptomics analysis demonstrated robust regionalization in both early- and late-stage patterned organoids.

Distinct spatial patterning and transcriptomic landscapes of human neural organoids by localized delivery of morphogens

VIPR1 acts as an enteric neural checkpoint that suppresses intestinal stem cell-driven epithelial regeneration and exacerbates colitis Li et al. reveal VIPR1 as an ISC-intrinsic neuronal checkpoint through which VIP-producing enteric neurons restrain ISC-driven epithelial regeneration via an ERK-Notum-Wnt/β-catenin inhibitory axis. Blocking epithelial VIPR1 releases this neural brake, enhancing mucosal regeneration and alleviating colitis.

VIPR1 acts as an enteric neural checkpoint that suppresses intestinal stem cell-driven epithelial regeneration and exacerbates colitis

Prevention of transgene silencing during human pluripotent stem cell differentiation Stable transgene expression remains challenging during human pluripotent stem cell differentiation. Wernig and colleagues show that combining CAG/Ubc promoters with WPRE prevents transgene silencing following both random and targeted integration. This work provides a broadly applicable genetic tool for studies requiring sustained transgene expression during differentiation of pluripotent stem cells.

Prevention of transgene silencing during human pluripotent stem cell differentiation

Engineered intestinal crypt geometry uncovers YAP1-dependent fetal-to-adult transition Using engineered scaffolds mimicking intestinal crypts, Maimets et al. show that tissue geometry drives epithelial maturation by regulating YAP activity. Crypt-like structures promote differentiation of fetal cells, providing insight into how form guides function and offering a platform for modeling intestinal development and repair.

Engineered intestinal crypt geometry uncovers YAP1-dependent fetal-to-adult transition

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

Chromatin Accessibility Dynamics during Chemical Induction of Pluripotency

Randomized phase 2b dose-escalation trial of stem cell therapy with laromestrocel for aging frailty Ruiz et al. present results of a phase 2 randomized trial of intravenous laromestrocel, a mesenchymal stem cell product, which improved the physical condition of patients with age-related clinical frailty after 9 months, compared with placebo. Reduced sTIE2 in blood provides a mechanistic link to improved vascular function and inflammaging.

Online Now! Randomized phase 2b dose-escalation trial of stem cell therapy with laromestrocel for aging frailty #stemcells

Minimizing far-extending chromatin perturbation in genome editing preserves stem cell identity Zhu et al. report that CRISPR editing displaces CTCF- and condensate-associated distal regulations, rewiring 3D genomic regulation. Even distal cleavage causes stem cell differentiation. The authors propose strategies to minimize chromatin disruption and preserve cell identity.

Online Now! Minimizing far-extending chromatin perturbation in genome editing preserves stem cell identity #stemcells

Pluripotent stem cell-derived CAR-NK progenitor therapy targets minimal residual disease and prevents relapse in leukemia models NK cell therapy lacks sustained efficacy in treating tumors. Wang and colleagues developed a pluripotent stem cell-derived induced NK lineage-committed progenitor (iNKP) cell therapy, which showed persisting iNK cells in vivo and reduced cancer relapse by eradicating MRD.

Online Now! Pluripotent stem cell-derived CAR-NK progenitor therapy targets minimal residual disease and prevents relapse in leukemia models #stemcells

Losing sleep over #iPSC transgene silencing after differentiation?
Same here.

Bright in iPSCs.
Gone after differentiation.

Our paper in @cp-cellstemcell.bsky.social maps what actually keeps expression on👇
www.cell.com/cell-stem-ce...
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comBO: A combined human bone and lympho-myeloid bone marrow organoid for preclinical modeling of hematopoietic disorders Shen et al. report comBO, a combined human bone and bone marrow model that integrates osteolineage, vascular, stromal, and hematopoietic compartments in a single hiPSC-derived organoid system. comBO supports primary patient cells for preclinical disease modeling, identifying and validating MIF as a targetable inflammatory axis in myeloma-comBO chimeroids.

Online Now! comBO: A combined human bone and lympho-myeloid bone marrow organoid for preclinical modeling of hematopoietic disorders #stemcells

VIPR1 acts as an enteric neural checkpoint that suppresses intestinal stem cell-driven epithelial regeneration and exacerbates colitis Li et al. reveal VIPR1 as an ISC-intrinsic neuronal checkpoint through which VIP-producing enteric neurons restrain ISC-driven epithelial regeneration via an ERK-Notum-Wnt/β-catenin inhibitory axis. Blocking epithelial VIPR1 releases this neural brake, enhancing mucosal regeneration and alleviating colitis.

Online Now! VIPR1 acts as an enteric neural checkpoint that suppresses intestinal stem cell-driven epithelial regeneration and exacerbates colitis #stemcells

Distinct spatial patterning and transcriptomic landscapes of human neural organoids by localized delivery of morphogens Kim and colleagues developed a passive diffusion morphogen gradient generator that establishes a steep exogenous spatial gradient for organoid patterning. This approach creates distinct dorsal-ventral or rostral-caudal patterns within individual organoids. Spatial transcriptomics analysis demonstrated robust regionalization in both early- and late-stage patterned organoids.

Online Now! Distinct spatial patterning and transcriptomic landscapes of human neural organoids by localized delivery of morphogens #stemcells

Prevention of transgene silencing during human pluripotent stem cell differentiation Stable transgene expression remains challenging during human pluripotent stem cell differentiation. Wernig and colleagues show that combining CAG/Ubc promoters with WPRE prevents transgene silencing following both random and targeted integration. This work provides a broadly applicable genetic tool for studies requiring sustained transgene expression during differentiation of pluripotent stem cells.

Online Now! Prevention of transgene silencing during human pluripotent stem cell differentiation #stemcells

Engineered intestinal crypt geometry uncovers YAP1-dependent fetal-to-adult transition Using engineered scaffolds mimicking intestinal crypts, Maimets et al. show that tissue geometry drives epithelial maturation by regulating YAP activity. Crypt-like structures promote differentiation of fetal cells, providing insight into how form guides function and offering a platform for modeling intestinal development and repair.

Online Now! Engineered intestinal crypt geometry uncovers YAP1-dependent fetal-to-adult transition #stemcells

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