Developmental cell最新文献

Generating functional β cells from stem cells remains a major challenge in regenerative medicine due to the incomplete recapitulation of human pancreatic development in vitro. By integrating newly generated human single-cell RNA sequencing (RNA-seq) datasets (Carnegie stages 10-15) with existing data, we mapped gene co-expression networks (GCNs) underlying pancreatic lineage progression in humans and mice. We observed significant species-specific differences in GCN robustness and dorsal-ventral propensity for progenitor development. Benchmarking three common differentiation protocols against the in vivo datasets showed that they fail to reproduce human-like GCNs, thereby limiting stem cell-derived insulin-secreting β cell (SC-β cell) induction efficiency. To address this, we developed a protocol that reconstructs human pancreatic GCN dynamics, shortens the induction period to 19 days, and achieves up to ∼70% β cell content. SC-islets generated with this method significantly alleviated diabetic symptoms and maintained mature β cell function after transplantation in mice. These findings bridge in vivo mechanisms and in vitro differentiation, advancing stem cell-based therapies.

The human brain stands out for the scale of cellular and morphological complexity across anterior-posterior domains. Modeling the entire neuraxis is therefore essential to comprehend human neural development and disease. Brain organoids commonly recapitulate anterior regions due to the propensity of neural progenitors to acquire telencephalic identities and self-organize into cortical layers. In the embryo, posterior brain patterning is orchestrated by organizers, signaling centers positioned at anterior-posterior locations that are rarely induced in vitro. Several strategies have been developed to reproduce organizer signals, employing small molecules and recombinant morphogens, thereby expanding the in vitro repertoire of human neural identities. Despite this, posterior models do not yet reproduce the morphological complexity of their in vivo counterparts. In this review, we discuss how this discrepancy may stem from the inability to recapitulate the spatiotemporal dynamics of organizer activity and how recent technologies can balance guided differentiation and self-organization, enhancing the fidelity of human brain organoid models.

Sprouting angiogenesis and blood vessel stabilization require precise coordination between endothelial cells (ECs) and pericytes. Bone Morphogenic Protein 9 (Bmp9), whose signaling through activin receptor-like kinase 1 (Alk1) is dysregulated in several diseases, was thought to regulate these processes by independently activating Notch target genes in an additive fashion with canonical Notch signaling. Here, through predictive computational modeling validated in mice, zebrafish, and human cell lines, we uncover that Bmp9 enhances Notch activity synergistically by upregulating Lunatic Fringe (Lfng) in ECs. Specifically, Bmp9-induced Lfng enhances Notch receptor activation, most strongly when Delta-like ligand 4 (Dll4) is also present. This Lfng regulation alters vessel branching by modulating the timing of EC phenotype selection and rearrangement during angiogenesis. Lfng also contributes to pericyte-driven vessel stabilization by mediating Jagged1 upregulation in Bmp9-stimulated ECs. In summary, Bmp9-upregulated Lfng enhances Dll4-Notch1 signaling in ECs and Jag1-Notch3 activation in pericytes, shaping angiogenic sprouting and stabilization outcomes.

Calcium (Ca) availability is vital for optimal plant growth and immune signaling, yet the underlying mechanisms remain elusive. Here, we reveal that Arabidopsis vacuolar H⁺-pyrophosphatase (AVP1)-regulated cytosolic inorganic pyrophosphate (PPi) homeostasis governs leaf growth by maintaining cellulose synthesis to suppress autoimmune activation upon Ca deficiency. Ca deficiency reduces the AVP1 abundance, while AVP1 eliminates excess cytosolic PPi, which impairs guanosine triphosphate-dependent microtubule assembly and reduces cellulose synthase 3-mediated cellulose synthesis. This cell-wall disruption activates isochorismate synthase 1-mediated salicylic acid production, triggering autoimmune responses and inhibiting new leaf growth. Enhancing PPi hydrolysis genetically improves plant growth tolerance to low Ca availability (low-Ca). The link between Ca-dependent PPi metabolic regulation, autoimmunity, and leaf growth is conserved in tomato, highlighting the broad relevance of AVP1 and PPi homeostasis in plant resilience. Our findings offer potential strategies for improving crop tolerance to nutrient-limited environments.