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Lineage and Organ Signals Sequentially Build Organ Intrinsic Nervous Systems [Spatial Transcriptomics]

ABSTRACT: Organ intrinsic nervous systems (OINSs) are critical components of the body–brain axis, coordinating visceral organ function with systemic physiological control. Despite their importance, how these distinct neural architectures arise from a common neural crest cell (NCC) origin has remained unclear. Here, we present a systems-level, cross-organ analysis of OINS development, integrating lineage tracing, 3D imaging, single-cell transcriptomics, and genetic perturbations across heart, pancreas, intestine, and lungs. We show that differences in NCC migratory trajectories prefigure the spatial architecture of OINSs, laying the foundation for organ-specific patterning. In contrast, molecular identity emerges largely in response to local environments, indicating that extrinsic cues play a major instructive role. Using in vitro co-cultures, we demonstrate that organ-derived cues reprogram intrinsic neurons toward organ-specific transcriptional profiles and direct neuronal differentiation, with extracellular matrix (ECM) contact identified as a central mediator. In vivo, ECM–integrin signaling supports intrinsic cardiac neuron neurogenesis, while ECM crosslinking stabilizes their stereotyped ganglionic organization. Together, these findings reveal that OINS diversity arises through a dual logic: lineage programs prefigure spatial frameworks, while organ-specific cues instruct final molecular identities and architectural precision. This work establishes a conceptual paradigm for how organs actively build their own nervous systems, illuminating principles that underpin body–brain integration.

ORGANISM(S): Mus musculus

PROVIDER: GSE322766 | GEO | 2026/03/16

REPOSITORIES: GEO

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Project description:Cholangiocarcinoma (CCA) is a type of liver cancer with an aggressive phenotype and dismal outcome in patients. Current treatment options are limited, with surgical resection or transplantation the only possibility with curative intent. This becomes unavailable if CCA metastasizes to distant organs, most commonly lung and lymph nodes, which in turn drastically reduces overall survival. Clinically, these metastatic sites have a distinct impact on prognosis and survival, however mechanistic insight is lacking. This is partly due to currently available models that fail to mimic the complexity of tissue-specific environments for metastatic CCA. To create an in vitro model in which interaction between epithelial tumor cells and their surrounding extracellular matrix (ECM) can be studied in a metastatic setting, we combined patient-derived CCA organoids (CCAOs) (n=3) with decellularized human lung (n=3) and decellularized human lymph node (n=13). Decellularization resulted in removal of cells while preserving ECM structure and retaining important characteristics of the tissue origin. This includes a tissue-specific ECM protein signature and macro and micro-scale mechanical properties, which reveal the local heterogeneity of the ECM. After recellularization, gene expression analysis showed metastasis-related processes, including epithelial-to-mesenchymal transition, cancer stem cell plasticity, and ECM production, are significantly influenced by the ECM in an organ-specific manner. Furthermore, we find that CCAOs exhibit significant differences in migration and proliferation dynamics depending on metastatic site, the original patient tumor, and donor of target organ. Thus, CCA metastatic outgrowth is dictated both by the tumor itself as well as by the ECM of the target organ. In conclusion, convergence of CCAOs with its organ-specific location of metastasis, obtained by decellularization, provides a valuable tool for research on metastatic colonization in CCA.

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Lineage and Organ Signals Sequentially Build Organ Intrinsic Nervous Systems [Spatial Transcriptomics]

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