Cell Stem Cell

Human PSC-derived organoids model sympathetic ganglion development and its functional crosstalk with the heart Sympathetic ganglia control vital body functions, yet their modeling is challenging. Xiang and colleagues developed hPSC-derived organoids that recapitulate the sympathetic ganglia and their functional connection with the heart. These findings provide a model for studying human sympathetic ganglia, sympathetic control of target organs, and related diseases.

Online Now! Human PSC-derived organoids model sympathetic ganglion development and its functional crosstalk with the heart #stemcells

When the heart calls for help: Clusterin reprograms immunity to enable regeneration Adult mammalian hearts exhibit limited regenerative capacity. Fan et al. report that neonatal cardiomyocyte-derived clusterin competes for macrophage Toll-like receptor 4 to suppress inflammation and induces reparative polarization. This cardio-immune dialogue activates BMP2 signaling to stimulate cardiomyocyte proliferation, reframing inflammation as a cooperative driver of heart repair.

When the heart calls for help: Clusterin reprograms immunity to enable regeneration

Unlocking human brain networks by assembling circuits in vitro and in vivo In this issue of Cell Stem Cell, Wang et al. generate human nucleus basalis of Meynert organoids (hnbMOs), establish a human-specific cholinergic projection system in transplanted assembloids, and identify projection deficits in Down syndrome-derived assembloids. This study provides a valuable model for investigating nbM-related neural circuits and neurological disorders.

Unlocking human brain networks by assembling circuits in vitro and in vivo

An exploratory proposal for a revision to the 14-day rule in the regulatory context of China Tan et al. propose revising the 14-day rule for human embryo research, suggesting an extension to Carnegie Stage 12 under a strict oversight framework to enable critical developmental studies while upholding ethical standards in China.

An exploratory proposal for a revision to the 14-day rule in the regulatory context of China

Optimizing translational efficiency in stem cell clinical research Through a comprehensive analysis of stem cell clinical research in China, the authors reveal robust yet uneven translational linkages between IITs and INDs and propose governance reforms to reduce redundancy, enhance efficiency, and better align exploratory research with regulatory and industrial pathways.

Optimizing translational efficiency in stem cell clinical research

The evolution of microglia replacement: A new paradigm for CNS disease therapy Microglia are important immune cells in the brain. Mutations in microglia cause microgliopathies. Microglia replacement has emerged as a groundbreaking therapeutic paradigm that enables correction of pathogenic mutations and offers a promising avenue for treating brain diseases. This perspective article comprehensively reviews the evolution and application of microglia replacement.

The evolution of microglia replacement: A new paradigm for CNS disease therapy

👩‍🚀 What are the health effects of space on astronauts? Our Catriona Jamieson, MD, PhD, sheds light on the topic in a new @cp-cellstemcell.bsky.social article. Her work — the 1st comprehensive study of stem cell health in astronauts — provides answers NASA Twins couldn't: bit.ly/3KsuyLe

Space-associated stem cell hallmarks of aging and resilience in astronauts Hematopoietic stem and progenitor cell functionally organized multi-omics aging and resilience (HSPC-FOMA-R) analyses of 9 astronauts before, during, and after ISS missions revealed hallmarks of accelerated aging, including reduced self-renewal and telomere maintenance, mitochondrial dysfunction, and genomic instability with clonal mutations together with cytokine and retrotransposon deregulation.

Space-associated stem cell hallmarks of aging and resilience in astronauts

Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells Arif et al. show that lysosomes in aged HSCs are hyperacidic and dysfunctional, and that lysosomal alterations are central to HSCs’ decline with age. cGAS-STING signaling, driven by misprocessed mtDNA, mediates inflammation in old HSCs. Notably, inhibition of v-ATPases restores lysosomal integrity, reduces inflammation, and improves aged HSCs’ function.

Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells

Macro-scale, scaffold-assisted model of the human bone marrow endosteal niche using hiPSC-vascularized osteoblastic organoids Li et al. present a 3D in vitro bone marrow model that faithfully captures phenotypic, structural, and functional features of human endosteal bone marrow niches, enabling the study of pathophysiological interactions between hematopoietic stem and progenitor cells and their microenvironment in fully human settings.

Macro-scale, scaffold-assisted model of the human bone marrow endosteal niche using hiPSC-vascularized osteoblastic organoids

Injury-induced Clusterin+ cardiomyocytes suppress inflammation and promote regeneration in neonatal and adult hearts by reprogramming macrophages Zeng and colleagues identify Clu+ cardiomyocytes as key regenerative drivers that orchestrate a cardio-immune circuit to resolve inflammation and promote CM proliferation, highlighting CLU as a therapeutic target and offering translational insights for myocardial infarction repair in adults.

Injury-induced Clusterin+ cardiomyocytes suppress inflammation and promote regeneration in neonatal and adult hearts by reprogramming macrophages

Generation of human nucleus basalis organoids with functional nbM-cortical cholinergic projections in transplanted assembloids The nucleus basalis of Meynert (nbM) regulates cortical function and cognition. Liu and colleagues report a method for creating human nbM organoids (hnbMOs) containing cholinergic projection neurons that form functional connections with the cortex. This work provides a model to investigate nbM circuits and cholinergic dysfunction in neurological disorders.

Generation of human nucleus basalis organoids with functional nbM-cortical cholinergic projections in transplanted assembloids

Senolytic-sensitive p16Ink4a+ fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity The tumor stroma contains heterogenous cell types with senescent phenotypes. Lee et al. characterize a cancer-associated fibroblast (CAF) subtype characterized by p16INK4a expression and myofibroblastic differentiation that drives tumor plasticity and progression. p16INK4a+ CAF is druggable and presents a therapeutic target for highly aggressive lung adenocarcinoma.

Senolytic-sensitive p16Ink4a+ fibroblasts in the tumor stroma rewire lung cancer metabolism and plasticity

New issue alert! Featuring papers on cardio-immune interactions in heart regeneration, HSC aging and resilience in astronaut blood (cover), brain organoids with cholinergic circuitry, an organoid atlas & biobank, plus a macro-scale model of bone marrow endosteal niches. www.cell.com/cell-stem-ce...

If you are interested in aging and stem cells, check out our newly published work in Cell Stem Cell, in collaboration with Mickaël Ménager and his team at Institut Imagine (Paris, France), on a lysosome-based strategy that reverses aging in blood-forming stem cells.

A phenotypic brain organoid atlas and biobank for neurodevelopmental disorders Wang and colleagues present a phenotypic brain organoid atlas for neurodevelopmental disorders, revealing disease-specific cellular and molecular alterations that illuminate NDD pathogenesis. Integrating patient brain organoids, imaging, and exome sequencing, this resource provides a powerful platform to advance research and therapeutic discovery.

A phenotypic brain organoid atlas and biobank for neurodevelopmental disorders

Space-associated stem cell hallmarks of aging and resilience in astronauts Hematopoietic stem and progenitor cell functionally organized multi-omics aging and resilience (HSPC-FOMA-R) analyses of 9 astronauts before, during, and after ISS missions revealed hallmarks of accelerated aging, including reduced self-renewal and telomere maintenance, mitochondrial dysfunction, and genomic instability with clonal mutations together with cytokine and retrotransposon deregulation.

Online Now! Space-associated stem cell hallmarks of aging and resilience in astronauts #stemcells

Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells Arif et al. show that lysosomes in aged HSCs are hyperacidic and dysfunctional, and that lysosomal alterations are central to HSCs’ decline with age. cGAS-STING signaling, driven by misprocessed mtDNA, mediates inflammation in old HSCs. Notably, inhibition of v-ATPases restores lysosomal integrity, reduces inflammation, and improves aged HSCs’ function.

Online Now! Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells #stemcells

Macro-scale, scaffold-assisted model of the human bone marrow endosteal niche using hiPSC-vascularized osteoblastic organoids Li et al. present a 3D in vitro bone marrow model that faithfully captures phenotypic, structural, and functional features of human endosteal bone marrow niches, enabling the study of pathophysiological interactions between hematopoietic stem and progenitor cells and their microenvironment in fully human settings.

Online Now! Macro-scale, scaffold-assisted model of the human bone marrow endosteal niche using hiPSC-vascularized osteoblastic organoids #stemcells

Injury-induced Clusterin+ cardiomyocytes suppress inflammation and promote regeneration in neonatal and adult hearts by reprogramming macrophages Zeng and colleagues identify Clu+ cardiomyocytes as key regenerative drivers that orchestrate a cardio-immune circuit to resolve inflammation and promote CM proliferation, highlighting CLU as a therapeutic target and offering translational insights for myocardial infarction repair in adults.

Online Now! Injury-induced Clusterin+ cardiomyocytes suppress inflammation and promote regeneration in neonatal and adult hearts by reprogramming macrophages #stemcells

Boosting dopamine: Following the lineage toward Parkinson’s repair Low yields of dopamine neurons in human stem cell-derived neural grafts limit their potential for treating Parkinson’s disease. Zhang et al. develop a new three-dimensional differentiation method, informed and refined through careful clonal linage tracing of donor cells post-transplantation, to improve dopamine neuron purity of grafts, eliminating unwanted, off-target populations.

Boosting dopamine: Following the lineage toward Parkinson’s repair

RPE replacement therapy for dry AMD—early success in a phase 1/2 clinical trial The number of RPE transplantation clinical trials for dry AMD is increasing quickly, with groups using different stem cell sources, delivery approaches, and immune suppression. We discuss the recent success in a phase 1/2a clinical trial evaluating allogeneic RPE stem cell-derived RPE cells isolated from the RPE layer of human cadaveric eyes.

RPE replacement therapy for dry AMD—early success in a phase 1/2 clinical trial

Tissue regeneration: Unraveling strategies for resolving pathological fibrosis Tang and colleagues dissect cellular contributions and interplay among fibroblasts, epithelial progenitors, immune components, and vasculature in both regenerative and fibrotic responses to tissue injury. They also examine therapeutic strategies that navigate the complexities of immune mediators, fibrogenic myofibroblasts, and excess ECM with small-molecule targeting and various cell-based approaches.

Tissue regeneration: Unraveling strategies for resolving pathological fibrosis

N6-methyladenosine on L1PA governs the trans-silencing of LTRs and restrains totipotency in naive human embryonic stem cells Zhu and colleagues reported that METTL3 inhibition in naive hESCs upregulated 8C-associated transcripts, including LTRs, and promoted chromatin opening. Reducing m6A on primate-specific L1PA mimicked this transcriptome transition, influencing LTR binding and protein preferences for L1-mediated chromatin recruitment, particularly suppressing EP300 binding to ERV1 and enhancing KAP1 binding to ERVL-MaLR.

N6-methyladenosine on L1PA governs the trans-silencing of LTRs and restrains totipotency in naive human embryonic stem cells

Human heart-macrophage assembloids mimic immune-cardiac interactions and enable arrhythmia disease modeling O’Hern et al. present a novel human heart-macrophage assembloid platform generated by integrating hPSC-derived embryonic monocytes into heart organoids. These tissue-resident macrophages regulate cardiac development and conduction and, under chronic inflammation, recapitulate atrial fibrillation features, offering a powerful model to study immune-cardiac interactions and arrhythmia mechanisms.

Human heart-macrophage assembloids mimic immune-cardiac interactions and enable arrhythmia disease modeling

3D-generation of high-purity midbrain dopaminergic progenitors and lineage-guided refinement of grafts supports Parkinson’s disease cell therapy Chen and colleagues present a 3D differentiation method for the efficient and robust generation of mDAP-enriched donor cells from hPSCs. They mapped the clonal lineages between donor cells and their derivatives within grafts following transplantation, which facilitates further refinement of the differentiation method and the elimination of off-target lineage cells.

3D-generation of high-purity midbrain dopaminergic progenitors and lineage-guided refinement of grafts supports Parkinson’s disease cell therapy

EZHIP restricts noncanonical PRC2 binding and regulates H3K27me3 intergenerational inheritance and reprogramming Zeng et al. identify EZHIP as a critical epigenetic reprogramming factor in mouse early embryos, which promotes global erasure, intergenerational inheritance, and re-establishment of H3K27me3. They demonstrate that without EZHIP restriction, hyperactive PRC2 deposits promiscuous H3K27me3 across the genome, which paradoxically causes loss of H3K27me3-mediated imprinting memories and gene repression.

EZHIP restricts noncanonical PRC2 binding and regulates H3K27me3 intergenerational inheritance and reprogramming

Vitamin C conveys geroprotection on primate ovaries Jing et al. demonstrate that oral vitamin C supplementation delays ovarian aging in non-human primates, attenuating key aging hallmarks and rejuvenating the ovarian cellular and molecular profiles. These geroprotective effects are partially mediated through NRF2 pathway activation, supporting vitamin C as a translatable nutritional strategy to combat reproductive aging.

Vitamin C conveys geroprotection on primate ovaries

Crosstalk between tissue mechanics and BMP4 signaling regulates symmetry breaking in human gastrula models Brivanlou and colleagues used optogenetics to spatially control BMP4 expression in human stem cell models across different mechanical regimes. By combining these experiments with mathematical modeling, they dissected how biochemical signals and mechanical forces integrate to initiate symmetry breaking at the onset of gastrulation.

Crosstalk between tissue mechanics and BMP4 signaling regulates symmetry breaking in human gastrula models

Hypoxia promotes airway differentiation in the human lung epithelium Dong and colleagues uncover low oxygen-directed differentiation of human lung progenitors to airway rather than alveolar fate and show how the process is controlled by hypoxia-inducible factors. Hypoxia also converts differentiated alveolar cells into airway-like cells. Hypoxia is therefore both a developmental cue and a pathological factor in human lungs.

Hypoxia promotes airway differentiation in the human lung epithelium