Bratt-Leal et al. report the preclinical data supporting initiation of a clinical trial investigating autologous dopaminergic neuron precursor cell therapy for moderate to advanced Parkinson’s disease patients. Whole-genome sequencing and RNA-seq analysis underpin a quality control program to ensure safety and efficacy.

Zhang and colleagues established a patient-derived brainstem glioma organoid (BSGO) platform that preserved tumor microenvironment and enabled mechanistic and therapeutic discovery. They uncovered mechanism of H3K27M-driven tumor stemness in diffuse midline glioma and translated organoid-guided screening into personalized treatment, demonstrating the potential of intrathecal differentiation therapy.

Liu et al. demonstrate the clinical efficacy of the transformer base editor in one patient with SCD and three non-Chinese patients with TDT, achieving durable pan-cellular HbF induction, sustained elimination of VOCs, and persistent transfusion independence during follow-up.

Zhong and colleagues reveal a mechanism behind organ size control in development and regeneration. High IGF2 levels drive and coordinate rapid fetal and neonatal growth, while IGF2 silencing—upon postnatal Hippo signaling activation—limits growth and determines organ size. Restoring IGF2 expression enhances tissue repair and reverses age-related regenerative defects.

Endothelial cells instruct the early developmental program of human periosteum-derived callus organoids. Scalable organoid aggregates guide host-mediated regeneration through endochondral ossification, restoring critical-size skeletal defects.

Zhou and colleagues present Epi-Allele, an allele-specific epigenetic silencing strategy that rebalances allelic expression while preserving total gene output. In HCM models, Epi-Allele silences pathogenic alleles, induces compensatory upregulation of non-targeted alleles, and alleviates disease without causing therapeutic haploinsufficiency.

Blelloch and colleagues create genetically engineered universal human iPSCs, differentiate them into CCR7+ migratory dendritic cells, and dress them with tumor-derived MHC class I-antigen complexes to develop a personalized cancer vaccine. They validate the approach using cancer cell lines and matching patient tumor/blood samples, both in vitro and in vivo.

In a recent article in Nature Medicine, Chen et al. describe a first-in-human study using an ASO tag to deliver a SOD1 siRNA to the central nervous system (CNS), potentially achieving faster, more extensive, and better-tolerated SOD1-lowering in ALS patients.1

Traditional ex vivo hematopoietic stem cell (HSC) gene therapy faces manufacturing challenges. A recent study in Nature Biomedical Engineering demonstrates that antibody-engineered lipid nanoparticles achieve efficient and durable in vivo editing of HSCs in humanized mice, offering a promising therapeutic strategy for genetic blood diseases.

Liu et al. extend the application of transformer base editing of HBG1/2 promoters from transfusion-dependent β-thalassemia alone to one patient with sickle cell disease and three patients with geographically diverse β-thalassemia genotypes. The responses are meaningful, but scale, genomic surveillance, burden of cure, and access now define the translational test.

Patient-derived models of diffuse midline gliomas (DMGs) remain challenging for interrogating tumor biology and investigating novel therapeutics. Xie et al. develop a robust patient-derived brainstem glioma organoid (BSGO) platform, reveal an Activin B-ACVR2A signaling pathway that promotes DMG growth, and identify a promising triple intrathecal therapy to inhibit it.

The imprinted gene IGF2 is a well-characterized growth factor regulating organ proliferation during embryogenesis, while Hippo signaling has been demonstrated as an important regulator of organ size. This study by Zhong et al. mechanistically connects Hippo-controlled Igf2 expression in postnatal liver growth and regeneration.

Allele-selective silencing offers a strategy to suppress pathogenic alleles in dominant genetic disorders but may alter total gene dosage when the remaining allele does not compensate. Wang et al. show that SNP-guided epigenetic repression of mutant alleles can elicit compensatory expression from non-targeted alleles, highlighting considerations for future therapeutic applications.

(Cell Stem Cell 33, 1379–1397.e1–e8; August 6, 2026)

Klatt et al. show that phagocytosis-shielded, BaEVRLess-pseudotyped retroviral vectors transduce human hematopoietic stem cells directly in vivo in mobilized humanized mice. Chemoselection enriches gene-marked cells, and erythroid-specific knockdown of BCL11A and ZNF410 derepresses fetal globin to therapeutically relevant levels for sickle cell disease.

O’Hern et al. review advances in modeling immunity and tissue function using self-organizing hPSC-derived immunocompetent organoids, termed “immunoids.” They outline priorities for advancing the field, including standardization and biologically informed design principles to improve the physiological fidelity and translational value of next-generation models.

Bratt-Leal et al. report the preclinical data supporting initiation of a clinical trial investigating autologous dopaminergic neuron precursor cell therapy for moderate to advanced Parkinson’s disease patients. Whole-genome sequencing and RNA-seq analysis underpin a quality control program to ensure safety and efficacy.

Zhang and colleagues established a patient-derived brainstem glioma organoid (BSGO) platform that preserved tumor microenvironment and enabled mechanistic and therapeutic discovery. They uncovered mechanism of H3K27M-driven tumor stemness in diffuse midline glioma and translated organoid-guided screening into personalized treatment, demonstrating the potential of intrathecal differentiation therapy.

Liu et al. demonstrate the clinical efficacy of the transformer base editor in one patient with SCD and three non-Chinese patients with TDT, achieving durable pan-cellular HbF induction, sustained elimination of VOCs, and persistent transfusion independence during follow-up.

Zhong and colleagues reveal a mechanism behind organ size control in development and regeneration. High IGF2 levels drive and coordinate rapid fetal and neonatal growth, while IGF2 silencing—upon postnatal Hippo signaling activation—limits growth and determines organ size. Restoring IGF2 expression enhances tissue repair and reverses age-related regenerative defects.

Endothelial cells instruct the early developmental program of human periosteum-derived callus organoids. Scalable organoid aggregates guide host-mediated regeneration through endochondral ossification, restoring critical-size skeletal defects.

Zhou and colleagues present Epi-Allele, an allele-specific epigenetic silencing strategy that rebalances allelic expression while preserving total gene output. In HCM models, Epi-Allele silences pathogenic alleles, induces compensatory upregulation of non-targeted alleles, and alleviates disease without causing therapeutic haploinsufficiency.

Heart valve research has long lacked accessible human model systems. In this issue of Cell Stem Cell, He et al. and Voges et al. introduce complementary stem cell-derived valve models that recreate key aspects of valve development, tissue organization, and disease, opening new avenues to investigate disease mechanisms and therapies.

In this issue of Cell Stem Cell, Mesentier-Louro et al. use a multi-cellular integrated brain (miBrain) system to uncover mechanisms underlying the accumulation of neuronal α-synuclein (α-Syn) inclusions in APOE4 carriers.1 Their results suggest that APOE4 increases cholesterol levels and impairs lysosomal function in astrocytes, which release pathogenic α-Syn.

Two studies in this issue of Cell Stem Cell show that splenic extramedullary hematopoiesis in myelofibrosis develops within a remodeled hematopoietic, immune, and stromal environment. Austin et al. define its cellular states, whereas Dugué et al. reveal the spatial and temporal remodeling of the stromal niche.

Radiopharmaceutical theranostics remains constrained by tumors lacking a validated molecular target. Yang et al. engineer mesenchymal stem cells that sense tumor stiffness and respond by manufacturing a synthetic target in situ, making PET imaging and radionuclide therapy possible with existing clinical radioligands in tumors that were previously untargetable.

Schneider, Dussiau, and colleagues show that splenomegaly in myelofibrosis reflects active remodeling of the splenic stromal niche, not only extramedullary hematopoiesis. Reticular cell-driven complement activation disrupts lymphoid architecture and promotes fibrosis, identifying C3 as a targetable stromal axis.

Hoffman, Aifantis, Satija, and colleagues show that neoplastic extramedullary hematopoiesis in the spleens of advanced myelofibrosis patients is enriched for erythroid and megakaryocytes progenitors with aberrant inflammatory signatures at the transcriptional and chromatin levels. They identify remodeling of the splenic immune microenvironment (T, NK, and B cells) to dysfunctional phenotypes.

Blanchard and colleagues developed a multicellular integrated brain (miBrain) recapitulating α-synuclein pathogenic accumulation seen in carriers of the APOE4 genetic variant. They identified APOE4 astrocytes as key drivers of α-synuclein pathology. Pharmacological modulation of cholesterol restored disease phenotypes, pointing to cholesterol metabolism as a promising therapeutic target.

Many cancers lack suitable molecular targets for radiotheranostics. Liu and colleagues engineer mechanosensitive MSCs that convert tumor stiffness into synthetic expression of clinically actionable targets, thereby guiding radiopharmaceuticals for PET imaging and targeted radionuclide therapy. This programmable tumor-tagging strategy expands radiotheranostic opportunities to tumors previously considered non-targetable.

Tsai et al. describe a transient morphogen exposure strategy that establishes anterior and posterior organizers in neocortical organoids, driving long-term tissue polarization and areal molecular identities. This approach improves the modeling of neurodevelopmental disorders with area-specific neocortical phenotypes.

Ovarian aging may accelerate systemic aging beyond fertility decline. Jing et al. highlight the cellular and microenvironmental mechanisms associated with the ovarian-systemic axis and summarize multimodal interventions, including senolytics, metabolic reprogramming, regenerative medicine, and systemic approaches, and discuss their potential to preserve fertility and intercept ovarian contributions to systemic aging.

Human heart valve biology has been difficult to study in faithful in vitro models. Li and colleagues establish iPSC-derived valve assembloids that model key aspects of valves, identify mechanical force and shear stress as drivers of induction and ECM stratification, and model congenital and acquired valve diseases.

Voges and colleagues develop 3D bioengineered heart valve tissue from human pluripotent stem cells, allowing unprecedented access to study human valve disease pathogenesis and maturation processes.

Liu and colleagues developed TIGRa, an ultra-compact programmable gene activator that efficiently regulates multiple genes from a single construct. TIGRa supports cellular reprogramming and, when delivered by a single AAV, protects retinal neurons and preserves vision, highlighting its potential for genetic medicine.

(Cell Stem Cell 22, 893–908.e1–e6; June 1, 2018)

Hoffman, Aifantis, Satija, and colleagues show that neoplastic extramedullary hematopoiesis in the spleens of advanced myelofibrosis patients is enriched for erythroid and megakaryocytes progenitors with aberrant inflammatory signatures at the transcriptional and chromatin levels. They identify remodeling of the splenic immune microenvironment (T, NK, and B cells) to dysfunctional phenotypes.

Blelloch and colleagues create genetically engineered universal human iPSCs, differentiate them into CCR7+ migratory dendritic cells, and dress them with tumor-derived MHC class I-antigen complexes to develop a personalized cancer vaccine. They validate the approach using cancer cell lines and matching patient tumor/blood samples, both in vitro and in vivo.

Schneider, Dussiau, and colleagues show that splenomegaly in myelofibrosis reflects active remodeling of the splenic stromal niche, not only extramedullary hematopoiesis. Reticular cell-driven complement activation disrupts lymphoid architecture and promotes fibrosis, identifying C3 as a targetable stromal axis.

Blanchard and colleagues developed a multicellular integrated brain (miBrain) recapitulating α-synuclein pathogenic accumulation seen in carriers of the APOE4 genetic variant. They identified APOE4 astrocytes as key drivers of α-synuclein pathology. Pharmacological modulation of cholesterol restored disease phenotypes, pointing to cholesterol metabolism as a promising therapeutic target.

Many cancers lack suitable molecular targets for radiotheranostics. Liu and colleagues engineer mechanosensitive MSCs that convert tumor stiffness into synthetic expression of clinically actionable targets, thereby guiding radiopharmaceuticals for PET imaging and targeted radionuclide therapy. This programmable tumor-tagging strategy expands radiotheranostic opportunities to tumors previously considered non-targetable.

Tsai et al. describe a transient morphogen exposure strategy that establishes anterior and posterior organizers in neocortical organoids, driving long-term tissue polarization and areal molecular identities. This approach improves the modeling of neurodevelopmental disorders with area-specific neocortical phenotypes.

Ovarian aging may accelerate systemic aging beyond fertility decline. Jing et al. highlight the cellular and microenvironmental mechanisms associated with the ovarian-systemic axis and summarize multimodal interventions, including senolytics, metabolic reprogramming, regenerative medicine, and systemic approaches, and discuss their potential to preserve fertility and intercept ovarian contributions to systemic aging.

Human heart valve biology has been difficult to study in faithful in vitro models. Li and colleagues establish iPSC-derived valve assembloids that model key aspects of valves, identify mechanical force and shear stress as drivers of induction and ECM stratification, and model congenital and acquired valve diseases.

Voges and colleagues develop 3D bioengineered heart valve tissue from human pluripotent stem cells, allowing unprecedented access to study human valve disease pathogenesis and maturation processes.

Liu and colleagues developed TIGRa, an ultra-compact programmable gene activator that efficiently regulates multiple genes from a single construct. TIGRa supports cellular reprogramming and, when delivered by a single AAV, protects retinal neurons and preserves vision, highlighting its potential for genetic medicine.

Modeling of cardiac pathologies in tissue-engineered models is coming of age. Two independent studies by Reid et al.1 and Tani et al.2 present in-depth multi-phenomics data from a human cardiac organoid (hCO) model and explore hCOs and engineered heart tissues (EHTs) for modeling of diastolic dysfunction.

The generation of highly plastic cell states in colorectal cancer that are prone to metastatic dissemination involves complex epigenetic reprogramming, rather than new genetic traits. Goto et al. implement a serial orthotopic organoid transplantation framework to uncover the idea that losing Gata6, a guardian of the colonic lineage, promotes metastatic competence.

Cellular development unfolds across both space and time, with lineage history influencing cellular identity and tissue organization. In this issue of Cell Stem Cell, Jia et al. combine CRISPR lineage recording with spatial transcriptomics to reconstruct the clonal relationships and spatial organization of cells during mouse development and cancer progression.