A year of stem cell and developmental biology

The burden of liver disorders increases worldwide as does the necessity for new treatments. This Review discusses cell therapy as an alternative therapeutic strategy for liver transplantation, the pros and cons, and the future technological potential.

Bilateral grafts of cryopreserved human embryonic stem cell-derived dopaminergic neuron progenitor cells into the putamen of patients with Parkinson’s disease in a phase I clinical trial showed safety, improvements in off-drug motor function and graft survival at 18 months after transplant.

After transplantation into the brain of patients with Parkinson’s disease, allogeneic dopaminergic progenitors derived from induced pluripotent stem cells survived, produced dopamine and did not form tumours, therefore suggesting safety and potential clinical benefits for Parkinson’s disease.

Damotte et al. examine the utility of multiple measures of race and ancestry self-identification in the context of matching HLA for potential unrelated bone marrow donors with patients. They show that combining both race and geographic ancestry provides a better fit to HLA than either measure alone.

Jo, Inoue et al. use a machine-learning Bayesian causal forest algorithm to evaluate the effect of intensified myeloablative conditioning (MAC) on mortality following haematopoietic stem cell transplantation (HSCT). Intensified myeloablative conditioning (MAC) has heterogeneous effects on reducing mortality.

This protocol describes an ex vivo feeder-free culture method to differentiate genetically engineered hematopoietic stem and progenitor cells into allogeneic CAR-NKT cells for off-the-shelf cancer immunotherapy.

Human hematopoietic cells derived from pluripotent cells repopulate multiple blood lineages in mice.

Rettkowski, Romero-Mulero et al. show that myocardial infarction impacts bone marrow haematopoietic stem cells and leads to inflammatory myelopoiesis, which can be dampened by treatment with 4-oxo-retinoic acid, promoting cardiac recovery.

Hypoxia impairs the efficacy of stem cell-derived islet cell therapy, making it a potential barrier for treatment of type 1 diabetes. Wang et al. identify EDN3 as a key factor that preserves β cell identity and function in hypoxia, offering possible strategies to improve therapeutic outcomes.

Ishida et al. transplant Crispr/Cas9 gene edited MHC-II knockout or wild-type retinal pigment epithelium into cynomolgus monkey eyes. MHC-II knockout RPE engraft successfully with no infiltration of inflammatory cells.

Thomas, Marx et al. devise a live imaging approach to spatiotemporally dissect mouse ovulation ex vivo.

This resource integrates different human embryo datasets to create a transcriptional reference map of human embryonic development from zygote to gastrula.

This Resource uses deep learning-based tools to build a dynamic transcriptomic reference for mouse and human preimplantation development.

Hamazaki, Yang et al. report that an early pulse of retinoic acid robustly induces human gastruloids with a neural tube, segmented somites and more advanced cell types than conventional gastruloids.

This study reports an extended 2D gastruloid system for spatially modeling human mesoderm development.

Protocol for the generation of a stem cell-derived human postimplantation embryo model by the combination of embryonic and transgene-induced extraembryonic-like cells.

A multiomic atlas of human embryonic joint and cranium development enables detailed analysis of bone and cartilage maturation.

A comprehensive multi-omics reference atlas of prenatal human skin shows that innate immune cells crosstalk with non-immune cells to perform pivotal roles in skin morphogenesis, including the formation of hair follicles.

This Roadmap article discusses recent advances in the production and use of brain organoids to understand brain development and associated disorders. The path towards increasing organoid complexity and better maturation, to create more accurate and reproducible model systems, is outlined. Finally, the important ethical implications of these advances is discussed.

Nano et al. introduce a pipeline to generate meta-atlases of the human brain from existing single-cell datasets and extract gene modules linked to cell fate specification. Perturbing these programs in human cortical chimeroids validated their roles in cell type specification.

The mechanisms underlying human cell diversity are unclear. Here the authors provide a single-cell epigenome map of human neural organoid development and dissect how epigenetic changes control cell fate specification from pluripotency to distinct cerebral and retina neural types.

The transplantation of human cortical organoids in rats enables maturation and integration of human neural cells that can engage with the host circuitry, providing a framework to study alterations in morphology and physiology of patient-derived tissue.

This paper develops two approaches for multiplexing cortical organoids and SCanSNP, a method for deconvolving cell identities, to trace neurodevelopmental trajectories at scale.

This protocol can be used to generate three-dimensional vascularized bone marrow organoids from human induced pluripotent stem cells. The organoids contain key stromal and hematopoietic cell types and can be engrafted with normal and malignant cells from adult donors to model niche interactions.

We present a protocol for achieving efficient generation of hPSC-CM aggregates in suspension culture, emphasizing process simplicity, robustness and GMP compliance. The strategy promotes clinical translation and other applications that require large numbers of CMs.

Human pluripotent cells are differentiated into lung progenitors and alveolar type 1 cells.

Blood production depends on haematopoietic stem cells (HSCs) and progenitor cells, which are regulated by their microenvironment or niche. New lineage-tracing models and microscopy tools are increasing the understanding of HSC specification and function, and how stem cell–niche interactions are perturbed during ageing.

This Resource presents an atlas classifying the age-related changes in human hematopoietic stem and progenitor cells from gestation through aging.

Totani, Matsumura et al. characterize a subpopulation of aged hematopoietic stem cells with high mitochondrial mass and GPR183 expression that retain high regenerative potential, gain a selective survival advantage and maintain self-renewal capacity, emphasizing their adaptive importance.

Song et al. show that in young mice CD38 supports hematopoietic stem cell (HSC) proliferation by regulating Ca²⁺ signaling and mitochondrial activity. Conversely, the upregulation of CD38 during aging causes dysregulation of NAD metabolism, mitochondrial stress and HSC dysfunction.

Toghani, Gupte et al. identify semaphorin 4A as a cell-extrinsic factor that protects myeloid-biased hematopoietic stem cells from inflammaging, mainly produced by their progeny—neutrophils—and acting via a negative feedback loop.

Zeng, Shi, Han, Hu, Li, Wei et al. present a metabolic atlas covering 15 hematopoietic cell types from young and aged mice. By screening metabolites that are depleted with age, they identify that uridine treatment can restore function in aged hematopoietic stem cells.

Mouse stem cells that regenerate muscle are derived by organoid dedifferentiation of myoblasts.

Bernier, Hefendehl et al. describe a stromal progenitor cell population consisting of pericytes, venular smooth muscle cells and perivascular fibroblasts in the adult brain that modify their function and coordinate blood vessel repair following stroke.

The freshwater planarian S. mediterranea is an important model organism for regeneration research but its use in aging research is little explored and S. mediterranea is commonly referred to as immortal. Here Dai et al. report age-associated physiological and molecular changes in the sexual lineage of S. mediterranea, and global reversal of such changes after regeneration.

Matoba, Le, Valone et al. characterized context-dependent genetic effects on gene regulatory activity during Wnt stimulation, finding that genetic variant function during neurodevelopment patterning can lead to differences in adult brain traits.

The authors show PTEN mutations, which can cause both congenital hydrocephalus and autism spectrum disorder, disrupt CSF homeostasis and brain connectivity in mice. Reducing mTORC1 activation ameliorates ventricular enlargement and neuronal deficits.

Han et al. report the existence of neural stem cells (NSCs) outside the central nervous system and show that these peripheral NSCs display features similar to brain NSCs, including the ability to differentiate into mature neurons.

Loh et al. investigate the role of LRP5 mutations in adipose tissue biology. They demonstrate that LRP5 promotes lower-body fat distribution and enhances systemic and adipocyte insulin sensitivity, which suggests that pharmacological activation of LRP5 could prevent age-related fat redistribution and metabolic complications.

Depleting SUN1 and SUN2 proteins of the inner nuclear envelope halts adipogenic differentiation in mesenchymal stem cells via heterochromatic accrual on lineage genes independent of LINC complex function.

Jackson et al. provide insight into how metabolic adaptations that accompany cell state transitions drive reliance on exogenous nutrient availability, focusing on pyruvate as a key metabolite in central carbon metabolism.

The mitochondrial unfolded protein response is shown to inhibit pluripotency during somatic cell reprogramming and to inhibit the mesenchymal-to-epithelial transition through c-Jun-mediated histone acetylation.

Peroxisomes are essential but their role in cell fate regulation remains understudied. Here, the authors reveal that young and old peroxisomes are not equally distributed in asymmetrically dividing stem cells, and peroxisome inheritance influences daughter cell fate.

Zhang and colleagues identify the transcription factor GABPA as a regulator of zygotic genome activation, epiblast formation and naive pluripotency establishment.

Ubiquitin-specific peptidase 22 (USP22) is identified as a key chromatin-based barrier to human iPSC derivation through a chromatin-focused CRISPR-Cas9 screen.

Comparative analysis of 100+ PSC lines highlights biological differences between defined and undefined culture conditions. Standardization reduces PSC variability, maintains self-renewal, and enhances reproducibility with a role for Ca2+ signaling.

The pluripotency program is maintained by transcription factors from the Sox and POU families. Here they identify SOX and POU factors from unicellular relatives of animals and show that unicellular SOX can replace SOX2 to induce pluripotency, whilst unicellular POU differs from OCT4.