Human organoids provide increasingly sophisticated models of tissue-specific physiology and disease, but their use in studies of endocrine communication and gene regulation remains limited. Here, we examine how organoid-based systems may be developed to study inter-organ endocrine networks, using the vitamin D–FGF23–PTH axis as a representative example. This axis spans the intestine, liver, kidney, bone and parathyroid gland, and integrates hormonal feedback with transcriptional control of defined target genes. We distinguish self-organizing organoids, organoid-on-a-chip platforms and multi-organ microphysiological systems, as these classes differ substantially in their capacity to support endocrine exchange between tissues. We then discuss the physiological functions such a model would need to reproduce, including feedback regulation of PTH, CYP27B1, CYP24A1 and FGF23. Although several tissue modules and coupled culture systems have been reported, important gaps remain in the maturation, functional competence and quantitative integration of kidney, bone and parathyroid compartments. We further consider how single-cell multi-omics and perturbation-based approaches can connect endocrine signals with cell-type-specific regulatory mechanisms. In this context, we distinguish descriptive co-expression patterns from transcription-factor regulons and experimentally validated regulatory interactions. We outline an evidentiary framework that links ligand–receptor signaling to transcription-factor activity, cis-regulatory elements, target-gene regulation and functional perturbation. Finally, we propose practical criteria for evaluating inter-organ gene regulatory network platforms, including tissue-module competence, directional coupling, feedback-loop closure, physiological concentration ranges, regulatory resolution and reproducibility. These considerations define the experimental advances needed before multi-organ organoid systems can yield mechanistic insight into endocrine gene regulation and its perturbation in disease.
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Translational Research Using Human Organoids: Integrating Multi-Organ Communication and Gene Regulatory Networks
Author Information
Received: 19 Apr 2026 | Revised: 27 Aug 2026 | Accepted: 04 Sep 2026 | Published: 24 Sep 2026
Abstract
Keywords
human organoids | organoid-on-a-chip | multi-organ microphysiological systems | gene regulatory networks | single-cell multi-omics | personalized medicine
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