The Impact of Mechanical Cues on the Metabolomic and Transcriptomic Profiles of Human Dermal Fibroblasts Cultured in Ultrashort Self-Assembling Peptide 3D Scaffolds

Cells’
interactions with their microenvironment influence
their morphological features and regulate crucial cellular functions
including proliferation, differentiation, metabolism, and gene expression.
Most biological data available are based on in vitro two-dimensional (2D) cellular models, which fail to recapitulate
the three-dimensional (3D) in vivo systems. This
can be attributed to the lack of cell–matrix interaction and
the limitless access to nutrients and oxygen, in contrast to in vivo systems. Despite the emergence of a plethora of
3D matrices to address this challenge, there are few reports offering
a proper characterization of these matrices or studying how the cell–matrix
interaction influences cellular metabolism in correlation with gene
expression. In this study, two tetrameric ultrashort self-assembling
peptide sequences, FFIK and FIIK, were used to create in vitro 3D models using well-described human dermal fibroblast cells. The
peptide sequences are derived from naturally occurring amino acids
that are capable of self-assembling into stable hydrogels without
UV or chemical cross-linking. Our results showed that 2D cultured
fibroblasts exhibited distinct metabolic and transcriptomic profiles
compared to 3D cultured cells. The observed changes in the metabolomic
and transcriptomic profiles were closely interconnected and influenced
several important metabolic pathways including the TCA cycle, glycolysis,
MAPK signaling cascades, and hemostasis. Data provided here may lead
to clearer insights into the influence of the surrounding microenvironment
on human dermal fibroblast metabolic patterns and molecular mechanisms,
underscoring the importance of utilizing efficient 3D in vitro models to study such complex mechanisms.