Biological systems arise from heterogeneous processes spanning molecular, cellular, organismal, and environmental scales, making the organization of cross-scale interactions central to biological function. Understanding such systems requires not only modeling individual mechanisms, but also reasoning about how to connect such models across levels of description. Taking this meta-modeler's view means being explicit about the interfaces between models - the variables they share - and how their processes are coordinated across scales. Using the cell as a central case, I show how molecular processes assemble into a cellular interface - the set of variables through which a cell senses and acts on its environment - that defines which environmental differences are biologically relevant, constrains exchange, and determines when cell-level descriptions remain valid. I describe a set of recurring composition patterns, including cell-environment coupling, cell-cell coupling, disintegration of the cellular interface, biomolecular composition, autopoiesis, growth, division, development, and evolution. These patterns reveal how processes connect, coordinate, and reorganize across scales, and how organization breaks down when constraints fail. Because a cell must keep these interface variables within viability bounds to persist, the cellular interface also grounds a minimal notion of agency: the organization that maintains it is what lets the cell regulate its exchanges, adapt to changing conditions, and learn from its interactions with the environment. This work advances compositional systems biology as a framework for reasoning about multiscale biological systems and connecting diverse submodels, treating each interface as both a modeling choice and a testable biological hypothesis about which interactions matter - and, for the cell, as the point at which molecular processes become organized enough to regulate and maintain their own conditions.
Biological systems arise from heterogeneous processes spanning molecular, cellular, organismal, and environmental scales, making the organization of cross-scale interactions central to biological function. Understanding such systems requires not only modeling individual mechanisms, but also reasoning about how to connect such models across levels of description. Taking this meta-modeler’s view means being explicit about the interfaces between models – the variables they share – and how their processes are coordinated across scales. Using the cell as a central case, I show how molecular processes assemble into a cellular interface – the set of variables through which a cell senses and acts on its environment – that defines which environmental differences are biologically relevant, constrains exchange, and determines when cell-level descriptions remain valid. I describe a set of recurring composition patterns, including cell–environment coupling, cell–cell coupling, disintegration of the cellular interface, biomolecular composition, autopoiesis, growth, division, development, and evolution. These patterns reveal how processes connect, coordinate, and reorganize across scales, and how organization breaks down when constraints fail. Because a cell must keep these interface variables within viability bounds to persist, the cellular interface also grounds a minimal notion of agency: the organization that maintains it is what lets the cell regulate its exchanges, adapt to changing conditions, and learn from its interactions with the environment. This work advances compositional systems biology as a framework for reasoning about multiscale biological systems and connecting diverse submodels, treating each interface as both a modeling choice and a testable biological hypothesis about which interactions matter — and, for the cell, as the point at which molecular processes become organized enough to regulate and maintain their own conditions.
Tissue repair requires rapid transitions in cellular states and robust cellular communication between tissue-resident cells and infiltrating immune cells. After injury, the amplitude and temporal regulation of inflammation must be efficiently coordinated to support subsequent tissue repair. Single-cell RNA sequencing (scRNA-seq) technologies and computational data analysis approaches have generated predictions about cellular states and communication that control inflammation, thereby promoting wound healing. Using skin as a clinically relevant model, we discuss how scRNA-seq has advanced our understanding of mechanisms that regulate inflammation after injury. In this review, we provide a detailed description of validated markers used to identify distinct cellular populations in murine and human skin and discuss how scRNA-seq has deepened our understanding of mechanisms regulating inflammation during acute wound healing. We further describe insights gained from scRNA-seq data generated under pathological conditions associated with dysfunctional inflammation and delayed wound healing, such as diabetes and aging. Future validation of these computational predictions and overcoming limitations associated with single-cell transcriptomics will provide greater clinical relevance for this technology that has increased the depth and rate of scientific discovery.
The skin is a highly innervated organ in which neural circuits continuously interact with epithelial, immune, and stromal compartments to coordinate tissue function. Historically, sensory and sympathetic nerves were viewed primarily as conduits for environmental input and autonomic output. However, recent studies demonstrate that cutaneous nerves serve as epithelial stem cell niches across compartments and regulate homeostasis, regeneration, healing, and adaptation to environmental change. In this Review, we discuss how sensory and sympathetic innervation is established during skin development and how epithelial tissues actively instruct the formation, specialization, and maturation of cutaneous neural circuits. We then examine emerging evidence that sensory and autonomic nerves regulate epithelial stem cells via direct neurotransmitter signaling, as well as through neuroimmune and neurostromal interactions. These mechanisms enable neural circuits to integrate local environmental cues with systemic physiological signals, including temperature, stress, circadian rhythms, and metabolic state. We further explore how aging alters neuroepithelial interactions and discuss evidence that age-associated degeneration of cutaneous innervation may impair stem cell function and tissue resilience. In parallel, we review growing evidence for sex-dependent differences in neural regulation, highlighting studies in which males and females achieve similar physiological outcomes via distinct neuroimmune and neuroendocrine mechanisms. Together, these findings support a neuroepithelial model of skin in which neural circuits regulate stem cell behavior and tissue adaptation throughout the lifespan. Interactions among neural, epithelial, immune, and stromal networks across biological contexts, including development, regeneration, aging, and sex, may reveal conserved mechanisms with broad therapeutic potential for preserving tissue function and resilience.
