The cellular lining of a continuous fluid compartment: an interstitial cell atlas and the Interstitial Hydraulic Gating hypothesis

SUPERSEDED. This preprint presented a single combined manuscript. It has since been divided into two papers, deposited separately: "The cellular lining of a continuous fluid compartment: an interstitial cell atlas" (doi:10.5281/zenodo.22718017) and "Interstitial Hydraulic Gating: interstitial volume as a mechanical gate" (doi:10.5281/zenodo.22718547). The atlas has grown from thirteen to fifteen populations and now spans liver and synovium. Readers should use the two successor deposits. This record is retained for citation continuity.The interstitium was long treated as inert packing between epithelium, vasculature and parenchyma. Three lines of work have made that position untenable: direct visualization of fluid-filled interstitial spaces in living human tissue, evidence that these spaces are structurally continuous across tissue and organ boundaries, and the demonstration that solute clearance from the brain depends on advective flow through perivascular compartments continuous with them. Each describes a space. None resolves which cells build it, maintain it, or set its mechanical properties. This review assembles the cellular lining of that compartment. Thirteen named stromal and interstitial populations, spanning fascia, vasculature, lymphoid tissue, gut and meninges, are described across largely non-overlapping literatures whose communities rarely cite one another, producing marker collisions that propagate into single-cell annotation: fasciacytes, telocytes and adventitial fibroblasts share CD34/PDGFRA profiles; mesenchymal stromal cells overlap cultured fibroblast signatures; and a proposed fourth meningeal layer remains disputed. Populations are admitted here on one criterion, stated explicitly and applied throughout: a cell qualifies if it sets the mechanical or transport properties of a fluid-conducting interstitial compartment. Positive and negative markers, developmental origin, niche and molecular regulation are integrated for each population and for organ-specific derivatives in heart, lung, kidney, gut and skin. Applying that criterion yields a testable claim, developed before the atlas rather than after it. The Interstitial Hydraulic Gating hypothesis holds that interstitial volume, set by local matrix protein composition and systemic hydration, gates the patency of the axons, capillaries and perivascular conduits the interstitium bounds, so that compaction and edema are opposite failures of one gate rather than unrelated pathologies. Its central prediction is that regional vulnerability tracks the hydration-sensitivity of local matrix composition rather than the intrinsic properties of neurons or vessels. Competing cell-autonomous and aquaporin-centered accounts are stated alongside it, with the observations that would separate them. An interactive three-dimensional model of the compartment is deposited openly; Figures 3 and 4 are deterministic renderings of it, so the predictions can be reproduced or contradicted directly.