🧐 What if some clonal hematopoiesis develops not because of positively selected cells taking over, but because of progressive loss of healthy cells until only a few are left to produce blood?

Check out our new paper in Cell Stem Cell! 🧵👇

Rebuilding the bridge: Functional AVN cells for cardiac repair Directing the differentiation of human pluripotent stem cells into atrioventricular node-like cells is a critical strategy for restoring atrioventricular node dysfunction in patients. In this issue, Lohbihler et al. define a BMP2-driven protocol to engineer functional conduction bridges that recapitulate the heart’s native “gatekeeper” properties in vivo.

Rebuilding the bridge: Functional AVN cells for cardiac repair

Less is more: Reducing zinc to boost stem cell-derived islet function and survival Zinc is required for insulin packaging into secretory granules, yet reduced zinc transporter activity paradoxically enhances beta cell function. In this issue, Wang et al. show that pharmacologic inhibition of zinc transport in stem cell-derived islets activates AMPK signaling and improves maturation, hypoxia resistance, VEGFA expression, and graft performance.

Less is more: Reducing zinc to boost stem cell-derived islet function and survival

Turning drivers into regulators: In vivo CAR reprogramming of Tfh cells Autoimmune hepatitis (AIH) is a progressive, life-threatening liver disease that remains treated largely with broad immunosuppression. In this issue of Cell Stem Cell, Jing and colleagues reprogram follicular helper T (Tfh) cells in vivo into antigen-specific FOXP3⁺ CAR-Tfh cells to restore immune tolerance by rewiring core drivers of autoimmunity.

Turning drivers into regulators: In vivo CAR reprogramming of Tfh cells

A sound link: Hearing, neurogenesis, and cognition Hearing loss has been considered one of the key risk factors for cognitive decline and dementia. Liu et al. establish a causal link between hearing activity, hippocampal neurogenesis, and cognitive function and identify the locus coeruleus-norepinephrine system as the mediator.

A sound link: Hearing, neurogenesis, and cognition

Endogenous aldehydes: A driver of clonal hematopoiesis from within? Detoxification of endogenous aldehydes is critical for preserving genomic integrity in hematopoietic stem cells. In this issue, Kamimae-Lanning et al. show that excess formaldehyde can drive clonal hematopoiesis through attrition of blood-forming progenitors, accelerating neutral drift in the absence of known genetic drivers of positive selection.

Endogenous aldehydes: A driver of clonal hematopoiesis from within?

Reconstructing tumor tissues in 3D: From organoids to bioengineered niches Tumor tissue engineering has opened new avenues for cancer research. With an emphasis on gastrointestinal malignancies, we summarize capabilities and limitations of patient-derived and engineered organoid models. We then discuss how innovations in biomaterial design, biofabrication, microfluidics, benchmarking, and AI converge to better emulate tumor tissues and advance translational modeling.

Reconstructing tumor tissues in 3D: From organoids to bioengineered niches

Pre-adaptation of stem cell-derived islet organoids to hypoxia via zinc transportation inhibition drives angiogenesis Li and colleagues show that inhibiting zinc transportation activates AMPK in stem cell-derived islets, enhancing functional maturation, hypoxia tolerance, and graft vascularization. This pre-adaptation strategy overcomes ischemic graft failure, a major barrier to diabetes cell therapy, and offers a translatable approach to improve transplantation outcomes.

Pre-adaptation of stem cell-derived islet organoids to hypoxia via zinc transportation inhibition drives angiogenesis

Engineered MSCs enable bone marrow-targeted immunomodulation Zhang and colleagues developed a bone marrow-targeted, tumor-evasive cell vector that enhances systemic immunity without stimulating tumor growth. By delivering protective or immune-restorative signals directly to immune organs rather than to the tumor itself, their strategy reframes cancer therapy as systemic immune reprogramming instead of localized tumor attack.

Engineered MSCs enable bone marrow-targeted immunomodulation

Human pluripotent stem cell-derived atrioventricular node-like pacemaker cells exhibit biological conduction bridge properties Protze and colleagues report a new protocol for the generation of human pluripotent stem cell-derived atrioventricular node-like pacemaker cells (AVNLPCs) via BMP signaling. These AVNLPCs display key AVN conduction properties upon engraftment into guinea pig hearts, representing a promising advancement toward a biological conduction bridge for the treatment of heart block.

Human pluripotent stem cell-derived atrioventricular node-like pacemaker cells exhibit biological conduction bridge properties

Metabolite-induced DNA damage drives stochastic stem cell loss and clonal hematopoiesis Protection against endogenous formaldehyde is important for blood stem cells throughout life. By studying blood-specific knockout mice and Fanconi anemia patients, Kamimae-Lanning and colleagues reveal that clonal hematopoiesis can arise not just through selective drivers but also through stochastic stem cell attrition, uncovering an alternative pathway shaping blood aging and disease.

Metabolite-induced DNA damage drives stochastic stem cell loss and clonal hematopoiesis

Delighted to share that our study is now out @cp-cellstemcell.bsky.social www.cell.com/cell-stem-ce... Congrats to Dr. @federicamosti.bsky.social for the culmination of a beautiful thesis!

Auditory activity sustains adult neurogenesis and cognition through the locus coeruleus-norepinephrine system Liu et al. show that specific ablation of outer hair cells (OHCs) in mice results in cognitive impairment and defective adult hippocampal neurogenesis because of the attenuation of PnCvGluT2 to LCNEergic neuronal afferents. Notably, they demonstrate that stimulating these neuronal afferents can rescue cognitive decline caused by hearing loss.

Auditory activity sustains adult neurogenesis and cognition through the locus coeruleus-norepinephrine system

Species-specific chromatin architecture and neurogenesis mediated by a human enhancer How human-specific DNA changes shape brain development is poorly understood. Mosti et al. discover a human enhancer, HAR1984, which drives ETV5 and TRA2B expression via human-enriched chromatin interactions. ETV5-HAR1984 binding generates a positive regulatory feedback, promoting cortical neurogenesis across human and chimpanzee organoids and cortical size and folds in mice.

Species-specific chromatin architecture and neurogenesis mediated by a human enhancer

Paired patient-derived organoids reveal transcription factor-driven epigenetic remodeling in breast cancer metastasis Chen and colleagues establish paired patient-derived organoids to investigate how breast cancers evolve from primary tumors to metastases. They uncover chromatin-based regulatory states that drive tumor progression and reveal transcription factors that promote metastatic spread, providing new insight into cancer evolution and potential therapeutic vulnerabilities.

Paired patient-derived organoids reveal transcription factor-driven epigenetic remodeling in breast cancer metastasis

In vivo CAR-Tfh cell reprogramming restores tolerance in a mouse model of autoimmune hepatitis Zheng et al. develop a lipid nanoparticle platform to reprogram follicular helper T cells into regulatory CAR-Tfh cells in vivo. This strategy enables the coordinated suppression of pathogenic immune responses and restores liver immune tolerance in autoimmune hepatitis, highlighting a versatile immunotherapy approach for autoimmune disease.

In vivo CAR-Tfh cell reprogramming restores tolerance in a mouse model of autoimmune hepatitis

Perturb-seq uncovers pathological obstacles to direct cardiac reprogramming in vivo Cai et al. used a Perturb-seq platform to systematically identify in vivo pathological barriers to cardiac reprogramming in infarcted mouse hearts. Calreticulin emerged as the top-ranked inhibitory factor, reducing calcium to inactivate MEF2C. Targeting this pathway boosted induced cardiomyocyte efficiency and function, revealing a potent regenerative target.

Online Now! Perturb-seq uncovers pathological obstacles to direct cardiac reprogramming in vivo #stemcells

Engineered MSCs enable bone marrow-targeted immunomodulation Zhang and colleagues developed a bone marrow-targeted, tumor-evasive cell vector that enhances systemic immunity without stimulating tumor growth. By delivering protective or immune-restorative signals directly to immune organs rather than to the tumor itself, their strategy reframes cancer therapy as systemic immune reprogramming instead of localized tumor attack.

Online Now! Engineered MSCs enable bone marrow-targeted immunomodulation #stemcells

Preservation of chondrocyte microspheroids by local sustained hydrogen supply improves osteoarthritic cartilage repair He et al. discover that persistent H2 supply can preserve the viability and phenotype of transplanted chondrocytes in an unfavorable pathological microenvironment of osteoarthritis, and they construct a H2-releasing, chondrocyte-encapsulating hydrogel transplant, thereby realizing the rapid and efficient repair of sheep osteoarthritic cartilage defects and the reversal of osteoarthritic progression within 6 months.

Online Now! Preservation of chondrocyte microspheroids by local sustained hydrogen supply improves osteoarthritic cartilage repair #stemcells

SPTEdU-seq enables parallel optics-free newborn cell tracking and spatial total transcriptional dynamics in intact microenvironments Niu et al. present SPTEdU-seq, a spatial omics platform that enables co-profiling of newborn cell dynamics and full-length total transcriptomes at cellular resolution. This approach illuminates non-coding RNA regulations, spatial splicing, transient states, lineage trajectories, and cellular interactions in the contexts of regeneration, development, and tumor biology.

Online Now! SPTEdU-seq enables parallel optics-free newborn cell tracking and spatial total transcriptional dynamics in intact microenvironments #stemcells

Human pluripotent stem cell-derived atrioventricular node-like pacemaker cells exhibit biological conduction bridge properties Protze and colleagues report a new protocol for the generation of human pluripotent stem cell-derived atrioventricular node-like pacemaker cells (AVNLPCs) via BMP signaling. These AVNLPCs display key AVN conduction properties upon engraftment into guinea pig hearts, representing a promising advancement toward a biological conduction bridge for the treatment of heart block.

Online Now! Human pluripotent stem cell-derived atrioventricular node-like pacemaker cells exhibit biological conduction bridge properties #stemcells

Metabolite-induced DNA damage drives stochastic stem cell loss and clonal hematopoiesis Protection against endogenous formaldehyde is important for blood stem cells throughout life. By studying blood-specific knockout mice and Fanconi anemia patients, Kamimae-Lanning and colleagues reveal that clonal hematopoiesis can arise not just through selective drivers but also through stochastic stem cell attrition, uncovering an alternative pathway shaping blood aging and disease.

Online Now! Metabolite-induced DNA damage drives stochastic stem cell loss and clonal hematopoiesis #stemcells

Decoding the spatiotemporal development of the blood-brain barrier in human cortex Our study systematically reveals the initiation and establishment of the human blood-brain barrier (BBB) using spatiotemporal transcriptomics. By comparing human and mouse BBB development, we demonstrate the evolutionary conservation of this process and identify H2A.Z.1 as a key protein for BBB development.

Online Now! Decoding the spatiotemporal development of the blood-brain barrier in human cortex #stemcells

Species-specific chromatin architecture and neurogenesis mediated by a human enhancer How human-specific DNA changes shape brain development is poorly understood. Mosti et al. discover a human enhancer, HAR1984, which drives ETV5 and TRA2B expression via human-enriched chromatin interactions. ETV5-HAR1984 binding generates a positive regulatory feedback, promoting cortical neurogenesis across human and chimpanzee organoids and cortical size and folds in mice.

Online Now! Species-specific chromatin architecture and neurogenesis mediated by a human enhancer #stemcells

Auditory activity sustains adult neurogenesis and cognition through the locus coeruleus-norepinephrine system Liu et al. show that specific ablation of outer hair cells (OHCs) in mice results in cognitive impairment and defective adult hippocampal neurogenesis because of the attenuation of PnCvGluT2 to LCNEergic neuronal afferents. Notably, they demonstrate that stimulating these neuronal afferents can rescue cognitive decline caused by hearing loss.

Online Now! Auditory activity sustains adult neurogenesis and cognition through the locus coeruleus-norepinephrine system #stemcells

Paired patient-derived organoids reveal transcription factor-driven epigenetic remodeling in breast cancer metastasis Chen and colleagues establish paired patient-derived organoids to investigate how breast cancers evolve from primary tumors to metastases. They uncover chromatin-based regulatory states that drive tumor progression and reveal transcription factors that promote metastatic spread, providing new insight into cancer evolution and potential therapeutic vulnerabilities.

Online Now! Paired patient-derived organoids reveal transcription factor-driven epigenetic remodeling in breast cancer metastasis #stemcells

In vivo CAR-Tfh cell reprogramming restores tolerance in a mouse model of autoimmune hepatitis Zheng et al. develop a lipid nanoparticle platform to reprogram follicular helper T cells into regulatory CAR-Tfh cells in vivo. This strategy enables the coordinated suppression of pathogenic immune responses and restores liver immune tolerance in autoimmune hepatitis, highlighting a versatile immunotherapy approach for autoimmune disease.

Online Now! In vivo CAR-Tfh cell reprogramming restores tolerance in a mouse model of autoimmune hepatitis #stemcells

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