Cell-cell communication: new insights and clinical implications

Abstract

Multicellular organisms are composed of diverse cell types that must coordinate their behaviors through communication. Cell-cell communication (CCC) is essential for growth, development, differentiation, tissue and organ formation, maintenance, and physiological regulation. Cells communicate through direct contact or at a distance using ligand-receptor interactions. So cellular communication encompasses two essential processes: cell signal conduction for generation and intercellular transmission of signals, and cell signal transduction for reception and procession of signals. Deciphering intercellular communication networks is critical for understanding cell differentiation, development, and metabolism. First, we comprehensively review the historical milestones in CCC studies, followed by a detailed description of the mechanisms of signal molecule transmission and the importance of the main signaling pathways they mediate in maintaining biological functions. Then we systematically introduce a series of human diseases caused by abnormalities in cell communication and their progress in clinical applications. Finally, we summarize various methods for monitoring cell interactions, including cell imaging, proximity-based chemical labeling, mechanical force analysis, downstream analysis strategies, and single-cell technologies. These methods aim to illustrate how biological functions depend on these interactions and the complexity of their regulatory signaling pathways to regulate crucial physiological processes, including tissue homeostasis, cell development, and immune responses in diseases. In addition, this review enhances our understanding of the biological processes that occur after cell-cell binding, highlighting its application in discovering new therapeutic targets and biomarkers related to precision medicine. This collective understanding provides a foundation for developing new targeted drugs and personalized treatments.

Fig. 1

Milestone events of CCC research. Key events in the development of CCC were retrospectively summarized from 1951 to the present day. Detailed information on milestone events are narrated in this review

Fig. 2

Representative signal pathways of CCC. Cellular communication is the process of signal construction to signal transduction. The interactions of ligands and receptors usually affect cell metabolism and energy transformation of different cell types to maintain the normal function of organisms. Ligands are active substances capable of specifically binding to receptors. Receptors specifically recognize and bind to signaling molecules, converting them into intracellular signals to perform specific physiological functions. One of the major signaling pathways within the signal transduction pathway are GPCRs pathways, including PKA and PKC systems. The others are enzyme-coupled receptor pathways, including PKG and MAPK systems. AC adenylate cyclase, cAMP cyclic adenosine monophosphate, cGMP cyclic guanosine monophosphate, CO carbon monoxide, DAG diacylglycerol, ERK extracellular regulated protein kinases, GC guanylate cyclase, GDP guanosine-5’-diphosphate, GPCR G-protein-coupled receptor, GTP guanosine triphosphate, IP3 inositol trisphosphate, IP3R inositol trisphosphate receptor, MAPK mitogen-activated protein kinase, MEK mitogen-activated extracellular signal-regulated kinase, NO nitric oxide, Pi PIP2 phosphatidylinositol-4,5-bisphosphate, PKA protein kinase A, PKC protein kinase C, PKG protein kinase G, PLC phospholipase C

Fig. 3

Examples of some diseases caused by representative abnormal CCC. CCC is an essential process that profoundly influences an organism’s homeostasis, development, and disease processes. When cells fail to interact correctly or misinterpret molecular information, diseases typically manifest. a Tumor cells invade surrounding tissues and blood vessel walls, infiltrate into blood vessels and spread to other parts of the body along the circulatory system, then interact with original tissue niche cells and migrate to distant tissues to colonize and grow. b Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis: A pro-inflammatory environment initiates the production of ANCA by plasma cells as well as the priming of neutrophils through cytokines. c Roles of astrocytes and microglia in neurodegeneration: Danger signals or invading pathogens activate microglia to release pro-inflammatory cytokines, which act on astrocytes, which in turn are activated to release pro-inflammatory cytokines. d Pathogenesis of rheumatoid arthritis II: The major cell types and cytokine pathways involved in joint destruction. e The role of ILC2s in asthma pathogenesis: Allergens, viruses or helminths provoke the release of alarmins from the damaged epithelium and stimulate the GATA3⁺/RORa⁺ ILC2s to express type 2 cytokines. Interleukins-4, -5, and -13 cause IgE increase from plasma cells, eosinophil expansion, and airway hyper-responsiveness, respectively. f Mechanism of SARS-CoV-2 viral entry: SARS-CoV-2 uses its spike (S) protein to adsorb and penetrate cells. S1 binds to the receptor angiotensin-converting enzyme II (ACE2) on the cell membrane through its receptor binding domain (RBD), and S2 mediates the fusion of the viral envelope with the host, allowing the viral nucleocapsid to enter the cytoplasm. g Type I vs. type II diabetes: The destruction of the islet cells prevents them from producing insulin, preventing glucose from entering the cells and leading to type 1 diabetes. The reduced responsiveness of the body’s cells to insulin leads to insulin resistance, and the inability to properly use insulin to metabolize glucose results in type 2 diabetes. h Differential roles of microglia in the developing brain: During healthy brain development, microglia in its homeostatic state mediates the maturation of oligodendrocyte precursor cells (OPCs) into myelinating mature oligodendrocytes

Fig. 4

Representative experimental methods for studying CCC. Technologies to expand the molecular-level understanding of cell–cell interaction biology include a microscopy imaging, b chemical tagging, c mechanoforce, and Co-IP analysis, and d functional exploitation

Fig. 5

The timeline of single-cell and spatial omics and related CCC softwares. a Timeline of the key technologies for single-cell and spatial omics were retrospectively summarized from 2011 to the present day. Cell numbers reported in representative publications by publication date. A full table with corresponding cell numbers is available as Supplementary Table 1. SCT single-cell transcriptome, ST spatial transcriptome, SCP single-cell proteomics, SP spatial proteomics. b The history of various bioinformatics and computational methods developed to infer biological cell–cell communications based on single-cell omics data. SCT single-cell transcriptome, ST spatial transcriptome

Fig. 6

CCC networks inferred from single-cell omics. Intercellular communication networks can be inferred through various single-cell multi-omics techniques and methods. (1) CCC of single-cell transcriptome: gene expression matrices of different cell types are obtained by performing single-cell RNA-seq, and then clustering analysis is carried out to infer communication networks of various cell types. CCC of single-cell proteomics: a single-cell suspension is made after collecting samples such as liver, pancreas, lung and mouse brain which labeling with conjugated antibodies tagged with metal isotopes. Then cell–cell communication of different cell types is inferred through mass spectrometry flow cytometry and clustering analysis. (2) CCC of spatial proteomics: tissues are prepared on slides followed by labeling of conjugated antibodies tagged with metal isotopes and laser ablation, then protein expression map and CCC network is obtained by analysis of ion mass spectrometry. CCC of single-cell spatial transcriptome: by combining scRNA-seq with spatial localization, gene expression map of various cell types is obtained to infer CCCs in different spatial locations