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Results for “rho-Associated Kinases”

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PubMed2025

Dual-patterned pluripotent stem cells self-organize into a human embryo model with extended anterior-posterior patterning.

Human gastruloids are a powerful class of stem cell-derived models that recapitulate key features of early embryonic development, including symmetry breaking and the emergence of three germ layers1-3. However, they lack anterior embryonic structures and coordinated axial organization4-6. To address this limitation, we pre-patterned human pluripotent stem cells (hPSCs) by exposing them to either anterior (FGF2) or posterior (CHIR99021 [CHIR] & retinoic acid [RA]) cues. Upon mixing, these dual-patterned hPSCs interacted and self-organized into elongated structures with both anterior and posterior features-which we term anterior-posterior (AP) human gastruloids. Anteriorly pre-treated cells robustly intercalated into posteriorly pre-treated cells, collectively giving rise to a continuum of neural tissues-including a brain-like domain, a neural tube-like structure, and neuro-mesodermal progenitors (NMPs)-with segmented somites arrayed bilaterally. Single cell RNA sequencing (scRNA-seq) revealed that human AP gastruloids contain cell types resembling the midbrain-hindbrain boundary (MHB), regionalized hindbrain structures (i .e. rhombomeres 1-8), regionalized neural crest (i.e. cranial, vagal, trunk)7,8 and head mesoderm. Transcriptomic comparisons to primate embryos revealed that human AP gastruloids most closely resemble Carnegie stage 11 (CS11) embryos. While they lack a notochord and full dorsal-ventral polarity, human AP gastruloids recapitulate key spatial and temporal features of early neurulation and somitogenesis. Perturbation of folic acid metabolism or rho-associated kinase (ROCK) signaling induced spinal cord defects, phenocopying aspects of spina bifida and other neural tube defects, highlighting this model's potential for studying congenital disorders9. AP gastruloids may serve as a simple, robust, scalable platform for modeling coordinated human AP body axis development. More broadly, our results suggest that controlled interactions between differentially prepatterned progenitors can initiate self-organization of complex body axis features. The "pattern-and-mix" strategy may serve as a generalizable framework for assembling spatially organized stem cell models of mammalian development.

Journal Article↗

PubMed2026

Tanshinone IIA impairs platelet function and thrombus formation.

BACKGROUND: Tanshinone IIA (T-IIA) is a fat-soluble active ingredient derived from the traditional Chinese medicine Danshen and possesses cardioprotective property. However, its exact role in platelet function is unknown. OBJECTIVES: This study investigated T-IIA's role in platelet aggregation, granules release, spreading, clot retraction, as well as in vivo hemostasis and thrombus formation. METHODS: Human platelets were treated with different doses of T-IIA (10, 50, and 100 μM) to measure platelet function and activation. In addition, T-IIA was administrated into wild-type mice to evaluate hemostasis and thrombus formation. RESULTS: T-IIA significantly impaired platelet aggregation, adenosine triphosphate secretion, P-selectin expression, and spreading and clot retraction dose dependently without affecting the expression profiles of αIIbβ3 and glycoprotein VI or Ibα. Administration of T-IIA significantly prolonged mice tail bleeding time and inhibited arterial and venous thrombosis. Further analysis showed that T-IIA dose dependently reduced platelet reactive oxygen species generation. Quantitative proteomic and phosphoproteimic assays analyzing T-IIA-treated vs vehicle-treated platelets after stimulation identified dysregulated phosphorylation of several proteins, which were enriched in platelet activation. Among the downregulated phosphoproteins, Rho-associated protein kinase (ROCK)1, integrin β3, and talin1 exhibited the lower fold change of phosphorylation in T-IIA-treated platelets compared with those in vehicle-treated platelets. Consistently, T-IIA treatment inhibited the phosphorylation of ROCK1, p47phox, integrin β3, and talin1 in activated platelets. CONCLUSION: T-IIA impairs platelet function and thrombosis via inhibition of several signaling pathways including ROCK1/p47phox, β3, and talin1, implying that T-IIA may represent a promising therapeutic candidate for treating thrombotic diseases.

Animals↗

PubMed2026

Fasudil induces anti-inflammatory transcriptomic changes and increased proliferation in human trisomy 21 neural progenitor cells.

Down syndrome (DS) results from trisomy for human chromosome 21 and is the most frequent genetic cause of intellectual disability. No effective treatments currently exist that improve neurodevelopment and cognition. Atypical brain development in individuals with DS is apparent before birth, which suggests that the optimal time to begin administration of therapies is prenatally. Human neural progenitor cell (NPC) cultures provide a tractable in vitro model system to examine the effects of trisomy 21 (T21) on neurodevelopment and to measure the effects of pharmacological interventions. Here, we report the results of preclinical studies evaluating 24 candidate therapies. RNA sequencing analyses found that euploid and T21 NPCs showed different transcriptomic responses to five candidate pharmacotherapies. The Rho-associated coiled-coil kinase inhibitor fasudil increased proliferation of T21 NPCs, reduced expression of inflammatory pathway genes in T21 NPCs, and reduced markers of inflammation in LPS-stimulated microglial model systems. These results demonstrate that fasudil can alter multiple T21-associated abnormalities in a beneficial manner, suggesting that fasudil warrants further study as a candidate prenatal pharmacotherapy for DS.

Down Syndrome↗

PubMed2025

Design of precision therapeutics for a CKD risk allele by targeting Shroom3-Rock interaction.

Enhancer variants in Shroom3 associate with renal fibrosis (TIF), but with reduced albuminuria. Detailed mechanisms for these pleiotropic effects are unclear. Here, we focus on identifying the specific profibrotic Shroom3 motif and separating this from its anti-proteinuric function. Given the role for Rho-kinases (Rock) in TIF, and the interaction of Rock with Shroom3 ASD2-domain, we hypothesized that Shroom3-mediated Rock-activation is crucial for profibrotic function. To test this, we develop transgenic tools that overexpress wild-type- (WT-Sh3) or ASD2-domain deletion- Shroom3 (ASD2Δ-Sh3). During TIF, Shroom3 and Rock co-expression occur in injured tubular cells and fibroblasts. In tubular- & fibroblast- lines, ASD2Δ-Sh3 overexpression reduce Rock activation, and pro-fibrotic/pro-inflammatory transcripts downstream of TGFβ1/Wnt/Ctnnb1-signaling vs WT-Sh3. In vivo, inducible global-, or tubular-specific-, but not fibroblast-specific-, ASD2Δ-Sh3 overexpression mitigate TIF, vs WT-Sh3 overexpression. Importantly, ASD2Δ-Sh3 mice do not develop albuminuria, while overexpression of a distinct Fyn-binding deficient mutant Shroom3 (FBDM-Sh3) induces albuminuria. We then develop small molecule inhibitors of Shroom3-Rock interaction (P2Is) and confirm Rock inhibition with these agents in WT-Sh3 cell lines. Our lead P2I from these studies, BT1137, mitigates Rock-activation, profibrotic signaling and TIF in WT-Sh3 mice. Hence, we delineate the profibrotic Shroom3 motif and develop therapeutics for kidney disease from Shroom3 excess.

Animals↗