Abstract
Cell-cell adhesion is crucial for maintaining cell functions and the integrity of tissue structure in organisms. However, cell-cell adhesion cues have not been effectively replicated in biomaterials and the associated mechanisms that enhance neural regeneration remained largely unexplored. Here, we present a diffusive N-cadherin functionalized hydrogel system, which provided cell-cell adhesion cues to modulate intercellular communications to significantly promote the formation of active neural network via thrombospondin-1 mediated neural communication and activation of TGF-β/Smad pathway. The dynamic assembly of N-cadherin at cell-hydrogel interface driven by adhered neurons effectively facilitated the reshaping of membrane protrusions to initiate intercellular adherens junctions. Further, this hydrogel system promisingly promoted neurological function recovery in rats following traumatic brain injury. Our study provides the principle of replicating diffusive cell adhesion molecules to mediate cell-cell adhesion in hydrogels, which may have broad applications in developing engineered biomaterials aimed at modulating cell fates in regeneration of various tissues.
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All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Information. RNA-seq data supporting the findings of this study are deposited in GEO (accession code GSE29157, [https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE297157]). The statistical analysis for all figures is provided in Excel format. Source data are provided with this paper.
References
Pepperkok, R. & Ellenberg, J. Innovation - High-throughput fluorescence microscopy for systems biology. Nat. Rev. Mol. Cell Biol. 7, 690–696 (2006).
Armingol, E., Baghdassarian, H. M. & Lewis, N. E. The diversification of methods for studying cell-cell interactions and communication. Nat. Rev. Genet. 25, 381–400 (2024).
Onesto, M. M., Kim, J. -i & Pasca, S. P. Assembloid models of cell-cell interaction to study tissue and disease biology. Cell Stem Cell 31, 1563–1573 (2024).
Stevens, A. J. et al. Programming multicellular assembly with synthetic cell adhesion molecules. Nature 614, 144–152 (2023).
Gumbiner, B. M. Cell adhesion: the molecular basis of tissue architecture and morphogenesis. Cell 84, 345–357 (1996).
Dalva, M. B., McClelland, A. C. & Kayser, M. S. Cell adhesion molecules: signalling functions at the synapse. Nat. Rev. Neurosci. 8, 206–220 (2007).
Scheiffele, P. Cell-cell signaling during synapse formation in the CNS. Annu. Rev. Neurosci. 26, 485–508 (2003).
Stogsdill, J. A. et al. Astrocytic neuroligins control astrocyte morphogenesis and synaptogenesis. Nature 551, 192–197 (2017).
Mauch, D. H. et al. CNS synaptogenesis promoted by glia-derived cholesterol. Sci. (N. Y., NY) 294, 1354–1357 (2001).
O’Shea, T. M. et al. Derivation and transcriptional reprogramming of border-forming wound repair astrocytes after spinal cord injury or stroke in mice. Nat. Neurosci. 27, 1505–1521 (2024).
Washbourne, P. et al. Cell adhesion molecules in synapse formation. J. Neurosci. 24, 9244–9249 (2004).
Belardi, B., Son, S., Felce, J. H., Dustin, M. L. & Fletcher, D. A. Cell-cell interfaces as specialized compartments directing cell function. Nat. Rev. Mol. Cell Biol. 21, 750–764 (2020).
Honig, B. & Shapiro, L. Adhesion protein structure, molecular affinities, and principles of cell-cell recognition. Cell 181, 520–535 (2020).
Wang, Y. C., Khan, Z., Kaschube, M. & Wieschaus, E. F. Differential positioning of adherens junctions is associated with initiation of epithelial folding. Nature 484, 390–393 (2012).
Campas, O., Noordstra, I. & Yap, A. S. Adherens junctions as molecular regulators of emergent tissue mechanics. Nat. Rev. Mol. Cell Biol. 25, 252–269 (2024).
Shigetomi, K., Ono, Y., Inai, T. & Ikenouchi, J. Adherens junctions influence tight junction formation via changes in membrane lipid composition. J. Cell Biol. 217, 2373–2381 (2018).
Barcelona-Estaje, E. et al. N-cadherin crosstalk with integrin weakens the molecular clutch in response to surface viscosity. Nat. Commun. 15, 8824 (2024).
Neville, G. M. et al. Interactions of choline and geranate (cage) and choline octanoate (caot) deep eutectic solvents with lipid bilayers. Adv. Funct. Mater. 34, 2306644 (2024).
Zhou, X., Moran-Mirabal, J. M., Craighead, H. G. & McEuen, P. L. Supported lipid bilayer/carbon nanotube hybrids. Nat. Nanotechnol. 2, 185–190 (2007).
Chooi, W. H. & Chew, S. Y. Modulation of cell-cell interactions for neural tissue engineering: Potential therapeutic applications of cell adhesion molecules in nerve regeneration. Biomaterials 197, 327–344 (2019).
Yang, J. et al. 3D bioprinted dynamic bioactive living construct enhances mechanotransduction-assisted rapid neural network self-organization for spinal cord injury repair. Bioact. Mater. 46, 531–554 (2025).
Basit, H., Lopez, S. G. & Keyes, T. E. Fluorescence correlation and lifetime correlation spectroscopy applied to the study of supported lipid bilayer models of the cell membrane. Methods 68, 286–299 (2014).
Drabik, D., Drab, M., Penic, S., Iglic, A. & Czogalla, A. Investigation of nano- and microdomains formed by ceramide 1 phosphate in lipid bilayers. Sci. Rep. 13, 18570 (2023).
Wei, D. et al. Magnetic on-off manipulated matrix mechanic vibration to enhance cell clutches-reinforcement and Ca2+ influx facilitating BMSCs neural differentiation and TBI repair. Chem. Eng. J. 484, 149521 (2024).
Hong, Y. et al. A strongly adhesive hemostatic hydrogel for the repair of arterial and heart bleeds. Nat. Commun. 10, 2060 (2019).
Axpe, E., Orive, G., Franze, K. & Appel, E. A. Towards brain-tissue-like biomaterials. Nat. Commun. 11, 3423 (2020).
Panda, A. et al. Direct determination of oligomeric organization of integral membrane proteins and lipids from intact customizable bilayer. Nat. Methods 20, 891–897 (2023).
Takeichi, M. The cadherin superfamily in neuronal connections and interactions. Nat. Rev. Neurosci. 8, 11–20 (2007).
Zobel, K., Choi, S. E., Minakova, R., Gocyla, M. & Offenhaeusser, A. N-Cadherin modified lipid bilayers promote neural network formation and circuitry. Soft Matter 13, 8096–8107 (2017).
Sloley, S. S. et al. High-frequency head impact causes chronic synaptic adaptation and long-term cognitive impairment in mice. Nat. Commun. 12, 2613 (2021).
Riquelme, D. et al. TRPM4 inhibition slows neuritogenesis progression of cortical neurons. Mol. Brain 17, 66 (2024).
Peng, J.-Y. et al. Ameliorating parkinsonian motor dysfunction by targeting histamine receptors in entopeduncular nucleus-thalamus circuitry. Proc. Natl. Acad. Sci. USA 120, e2216247120. (2023).
Gaertner, A. et al. N-cadherin specifies first asymmetry in developing neurons. Embo J. 31, 1893–1903 (2012).
Zhang, X. et al. Functional optic tract rewiring via subtype- and target-specific axonal regeneration and presynaptic activity enhancement. Nat. Commun. 16, 2174 (2025).
Nayak, D. et al. Development and crystal structures of a potent second-generation dual degrader of BCL-2 and BCL-xL. Nat. Commun. 15, 2742 (2024).
Spitz, A. Z. & Gavathiotis, E. Physiological and pharmacological modulation of BAX. Trends Pharmacol. Sci. 43, 206–220 (2022).
Nishitsuji, K. et al. Thrombospondin type 1 repeat-derived-mannosylated peptide attenuates synaptogenesis of cortical neurons induced by primary astrocytes via TGF-β. Glycoconj. J. 39, 701–710 (2022).
Nagai, J. et al. Hyperactivity with Disrupted Attention by Activation of an Astrocyte Synaptogenic Cue. Cell 177, 1280–1292 (2019).
Kuroki, H. et al. Effect of LSKL peptide on thrombospondin 1-mediated transforming growth factor β signal activation and liver regeneration after hepatectomy in an experimental model. Br. J. Surg. 102, 813–825 (2015).
Lund, H. et al. Fatal demyelinating disease is induced by monocyte-derived macrophages in the absence of TGF-β signaling. Nat. Immunol. 19, 1–7 (2018).
Sanyal, S., Kim, S. M. & Ramaswami, M. Retrograde regulation in the CNS:. Neuron-Specif. interpretations TGF-β Signal. Neuron 41, 845–848 (2004).
Park, K. K. et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science 322, 963–966 (2008).
Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005).
Safar, K. et al. Mild traumatic brain injury is associated with dysregulated neural network functioning in children and adolescents. Brain Commun. 3, fcab044-fcab044 (2021).
Chen, X. et al. Omega-3 polyunsaturated fatty acid supplementation attenuates microglial-induced inflammation by inhibiting the HMGB1/TLR4/NF-κB pathway following experimental traumatic brain injury. J. Neuroinflammation 14, 143 (2017).
Shen, B. et al. Ultrasoft bioadhesive hydrogel as a versatile platform for the delivery of basic fibroblast growth factor to repair traumatic brain injury. Chem. Eng. J. 483, 149017 (2024).
Liddelow, S. A. et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541, 481–487 (2017).
Bellver-Landete, V. et al. Microglia are an essential component of the neuroprotective scar that forms after spinal cord injury. Nat. Commun. 10, 518 (2019).
Zhai, Y. et al. Overexpressed ski efficiently promotes neurorestoration, increases neuronal regeneration, and reduces astrogliosis after traumatic brain injury. Gene Ther. 30, 75–87 (2023).
Cheng, C. et al. Thrombospondin-1 gene deficiency worsens the neurological outcomes of traumatic brain injury in mice. Int. J. Med. Sci. 14, 927–936 (2017).
Jamjoom, A. A. B., Rhodes, J., Andrews, P. J. D. & Grant, S. G. N. The synapse in traumatic brain injury. Brain 144, 18–31 (2021).
Song, H. et al. Traumatic brain injury recapitulates developmental changes of axons. Prog. Neurobiol. 217, 102332 (2022).
Ling, J. et al. Cell development enhanced bionic silk hydrogel on remodeling immune pathogenesis of spinal cord injury via m2 polarization of microglial. Adv. Funct. Mater. 33, 2213342 (2023).
Qin, T. et al. Local delivery of EGFR+NSCs-derived exosomes promotes neural regeneration post spinal cord injury via miR-34a-5p/HDAC6 pathway. Bioact. Mater. 33, 424–443 (2024).
Acknowledgements
Xiaoxuan Tang and Shuxuan Zhang contributed equally to this work. This work was financially supported by the National Natural Science Foundation of China (Project No. 32230057 (Y.M.Y.) and 32471412 (J.L.)), Natural Science Foundation of Jiangsu Province (Project No. BE2022766 (J.L.)), and Natural Science Foundation of the Higher Education Institutions of Jiangsu Province (22KJA310003 (J.L.)). Animals and animal feeding were provided by the Laboratory Animal Center of Nantong University.
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J.L., Y.F.G., and Y.M.Y. conceived the study design; X.X.T. and Y.F.G. performed the lipids fabrication; X.X.T., S.X.Z., and Y.X.L. fabricated the samples and performed the cell and animal experiments; M.K.L. and X.Y.S. participated in the cell experiments and performed data analysis; S.X.Z., C.H., Y.L.F., and X.W.Y. participated in the animal experiments. R.Z. and X.L.J. participated in revising the manuscript. Q.X.Z. provided technical support for whole-cell patch clamp recordings. J.L. and X.X.T. wrote the manuscript with discussions and improvements from all authors. J.L. and Y.M.Y. supervised the study and provided financial support.
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Tang, X., Zhang, S., Liu, M. et al. Hydrogel with cell-cell adhesion cues enhances neural regeneration. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68632-9
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DOI: https://doi.org/10.1038/s41467-026-68632-9
