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Extracellular Matrix Origin Directs Morphogenesis and Gene Regulation in Bioengineered Human Skin
Francesco Galardo1,2,3, Giorgia Imparato1, Costantino Casale1,3
1Istituto Italiano Di Tecnologia-IIT, Center for Advanced Biomaterials For Healthcare, Napoli, Italy.
Advanced Healthcare Materials
|January 28, 2026
Summary
Biofabricating functional human skin requires a native-like microenvironment. Endogenous extracellular matrix (ECM) supports proper gene expression and tissue architecture, unlike exogenous scaffolds, crucial for regenerative medicine.
Area of Science:
- Tissue Engineering
- Regenerative Medicine
- Biomaterials Science
Background:
- The cellular microenvironment, particularly the extracellular matrix (ECM), provides critical biochemical and mechanical cues for tissue development, repair, and homeostasis.
- The ECM instructs cell fate and function by guiding transcriptional programs.
- Understanding the impact of ECM origin is vital for successful biofabrication of functional tissues.
Purpose of the Study:
- To investigate the influence of endogenous versus exogenous extracellular matrix (ECM) on the biofabrication of human skin equivalents.
- To compare the transcriptional profiles and structural characteristics of skin constructs utilizing different ECM sources.
- To assess the suitability of various scaffolds for creating physiologically relevant skin tissue in vitro.
Main Methods:
- Biofabrication of human skin equivalents using fibroblast-assembled endogenous ECM and exogenous collagen-based scaffolds.
- Comparative analysis of full-thickness skin models.
- RNA sequencing to evaluate transcriptional trajectories.
- Histological assessment of tissue architecture, including the dermal-epidermal junction (DEJ).
Main Results:
- ECM origin significantly impacts transcriptional profiles and morphogenetic processes in skin equivalents.
- Skin equivalents with endogenously produced ECM exhibited physiologically relevant architecture and a well-organized DEJ.
- Constructs based on exogenous matrices showed abnormal epithelial expansion and failed to replicate key structural features.
Conclusions:
- Recapitulating the native extracellular matrix (ECM) is essential for generating functional human skin equivalents in vitro.
- The choice of scaffold material profoundly influences the development and structural integrity of engineered tissues.
- These findings have critical implications for scaffold selection in regenerative medicine and tissue engineering applications.
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