Two recent studies from the Silva and Hanna groups optimized chemical induction and culture conditions to derive extraembryonic lineages directly from embryonic stem cells (ESCs) without transgenes, enabling mouse stem cell-based embryo models (SCBEMs) to reproducibly advance to the E8.5–E8.75 stage.

The generation of stem-cell-based embryo models has ushered in a new era for human embryology, but improving their reproducibility and lineage fidelity has remained a challenge. In this issue of Cell Stem Cell, Chen et al. and Oura et al. develop refined strategies to assemble human post-implantation embryo models with greater accuracy and efficiency, setting a new standard for the field.

Chan et al. show that enteric neurons influence lipid metabolism in gastric cancer organoids, affecting dependencies on key enzymes. Using CRISPR screening and metabolic analysis, their work highlights how microenvironmental signals impact tumor metabolism and potential treatment targets in gastric cancer.

In this issue of Cell Stem Cell, Márquez-Valadez, Gallardo-Caballero, and Llorens-Martín1 report that adult hippocampal neurogenesis (AHN) is differentially disrupted in neuropsychiatric disorders. Their findings highlight the role of the neurogenic niche and lifestyle, supporting the view of human AHN as a dynamic process sensitive to biology and behavior.

In this issue of Cell Stem Cell, Huang et al. address the challenge of creating organoids that more closely replicate kidney spatial patterning and function. They develop region-specific progenitor assembloids mimicking native architecture. After transplantation into mice, which further promotes differentiation, they demonstrate functional and disease modeling capability.

Recent studies highlight microglial replacement as a promising therapeutic approach for neurological disease. Wu et al. demonstrated that transplanted bone marrow–derived cells halted ALSP progression, while Mader et al. introduced a strategy that avoids systemic bone marrow ablation toxicity and reduces immune rejection, collectively validating this strategy’s therapeutic potential.

Spaceflight provides a unique environment that profoundly influences stem cell biology. Experiments aboard the International Space Station (ISS) and in simulated microgravity have revealed altered stem cell proliferation, differentiation, and stress responses, unveiling possibilities for modeling impacts of spaceflight and harnessing microgravity for biomanufacturing. Stem cell-derived organoids and tissue models flown in space are yielding insights into development, disease, and aging mechanisms, while in-space biomanufacturing efforts demonstrate accelerated stem cell expansion and tissue formation for potential translational and clinical applications.

Fan et al. discovered that local cardiac injury triggers aberrant lysozyme 2 (Lyz2) expression in remote zones. Lyz2 acts as a remote-injury-triggered regulator of lysosomal degradation in endocardial cells, driving pathogenic extracellular matrix breakdown. Inhibiting the LYZ2-mediated injury response—via knockout or pharmacological lysosomal inhibition—confers rapid functional recovery of non-regenerative hearts.

Recapitulating the self-assembly of kidney progenitors, Huang, Medina, He, Zeng, and colleagues have developed mouse and human kidney progenitor assembloids, exhibiting enhanced cellular complexity, spatial organization, maturation, and functional capacity. These sophisticated models provide high-fidelity platforms for disease modeling and establish a robust foundation for kidney regenerative medicine.

Enhanced STAT3 activation combined with TGF-β inhibition reprograms human PSCs into cells specifying all early embryonic lineages. Upon 3D suspension culture, these cells self-organize within 6 days into post-implantation structures mimicking Carnegie stages 5–7 embryos, including gastrulation, with high morphological and molecular fidelity.

Márquez-Valadez and colleagues show that neuropsychiatric disorders alter the generation of new neurons in the adult human brain. Major depression, schizophrenia, and bipolar disorder disrupt early stages of hippocampal neurogenesis and its supportive environment, with lifestyle factors further modulating these effects—even in healthy individuals.

The field of medical science has relied on animal models to both establish fundamental biological principles and test new drugs prior to human administration for over 100 years. Given the significant differences between mice and humans, the relevance of these data has often been a concern to scientists. Recently, the development of induced pluripotent stem cells (iPSCs), organoids, and new bioengineering techniques along with advancing artificial intelligence (AI) has reached a tipping point—coming close to providing more reliable, relevant ways to understand human biology and help drug development.

Chan and colleagues use CRISPR screens in patient-derived tumor organoids to reveal metabolic vulnerabilities not seen in 2D and 3D spheroid models and identify potent inhibitors that target gastric cancer’s lipid metabolism. A neuron-cancer coculture screen found that ACC level predicts treatment efficacy, highlighting neuronal interaction in cancer lipid reliance.

Wu and colleagues developed inducible stem cell-based embryo models (iSCBEMs) that recapitulate key features of early post-implantation development, corresponding to Carnegie stages 5–6 (CS5–CS6). iSCBEMs offer a robust and accessible platform for studying this critical window, revealing new insights into the cellular origins of the yolk sac and extraembryonic mesenchyme.

Hanna and colleagues show that signaling pathway modulation amplifies the inherent flexibility of genetically unmodified mouse naive PSCs to adopt extra-embryonic cell fate potential. This endows them with the competence to generate up to E8.5–E8.75 transgene-free stem cell-derived embryo models (TF-SEMs) that complete gastrulation and initiate organogenesis within complex extra-embryonic compartments ex utero.

(Cell Stem Cell 29, 1669–1684.e1–e6; December 1, 2022)

Fan et al. discovered that local cardiac injury triggers aberrant lysozyme 2 (Lyz2) expression in remote zones. Lyz2 acts as a remote-injury-triggered regulator of lysosomal degradation in endocardial cells, driving pathogenic extracellular matrix breakdown. Inhibiting the LYZ2-mediated injury response—via knockout or pharmacological lysosomal inhibition—confers rapid functional recovery of non-regenerative hearts.

Recapitulating the self-assembly of kidney progenitors, Huang, Medina, He, Zeng, and colleagues have developed mouse and human kidney progenitor assembloids, exhibiting enhanced cellular complexity, spatial organization, maturation, and functional capacity. These sophisticated models provide high-fidelity platforms for disease modeling and establish a robust foundation for kidney regenerative medicine.

Retinal pigment epithelium (RPE) cell loss in dry age-related macular degeneration leads to progressive vision decline. Stern and others implanted adult RPE stem cell-derived RPE progeny at a 4-week progenitor stage of differentiation (RPESC-RPE-4W). First-in-human cohort 1 met primary safety endpoints, with greater visual improvement observed in worse-seeing eyes.

Enhanced STAT3 activation combined with TGF-β inhibition reprograms human PSCs into cells specifying all early embryonic lineages. Upon 3D suspension culture, these cells self-organize within 6 days into post-implantation structures mimicking Carnegie stages 5–7 embryos, including gastrulation, with high morphological and molecular fidelity.

Márquez-Valadez and colleagues show that neuropsychiatric disorders alter the generation of new neurons in the adult human brain. Major depression, schizophrenia, and bipolar disorder disrupt early stages of hippocampal neurogenesis and its supportive environment, with lifestyle factors further modulating these effects—even in healthy individuals.

The field of medical science has relied on animal models to both establish fundamental biological principles and test new drugs prior to human administration for over 100 years. Given the significant differences between mice and humans, the relevance of these data has often been a concern to scientists. Recently, the development of induced pluripotent stem cells (iPSCs), organoids, and new bioengineering techniques along with advancing artificial intelligence (AI) has reached a tipping point—coming close to providing more reliable, relevant ways to understand human biology and help drug development.