Transcriptomic analysis reveals dynamic molecular changes in skin induced by mechanical forces secondary to tissue expansion

Abstract

Tissue expansion procedures (TE) utilize mechanical forces to induce skin growth and regeneration. While the impact of quick mechanical stimulation on molecular changes in cells has been studied extensively, there is a clear gap in knowledge about sequential biological processes activated during long-term stimulation of skin in vivo. Here, we present the first genome-wide study of transcriptional changes in skin during TE, starting from 1 h to 7 days of expansion. Our results indicate that mechanical forces from a tissue expander induce broad molecular changes in gene expression, and that these changes are time-dependent. We revealed hierarchical changes in skin cell biology, including activation of an immune response, a switch in cell metabolism and processes related to muscle contraction and cytoskeleton organization. In addition to known mechanoresponsive genes (TNC, MMPs), we have identified novel candidate genes (SFRP2, SPP1, CCR1, C2, MSR1, C4A, PLA2G2F, HBB), which might play crucial roles in stretched-induced skin growth. Understanding which biological processes are affected by mechanical forces in TE is important for the development of skin treatments to maximize the efficacy and minimize the risk of complications during expansion procedures.

Transcriptome Profiling Reveals Important Transcription Factors and Biological Processes in Skin Regeneration Mediated by Mechanical Stretch

“…Skin undergoing stretch and relaxation is generally expected to experience injury and repair. Moreover, a controllable, moderate inflammatory response plays a significant role in promoting keratinocyte proliferation and initiating skin growth ( Ledwon et al, 2020 ). Chemokines then act on seven-transmembrane G-protein-coupled receptors and are characterized as leukocyte chemotactic signals, which exhibit differential chemotactic activity for different classes of leukocytes.…”

“…Meanwhile, some genes related to actin crosslink formation (TNNT2) were shown to be upregulated. TPM1, TPM2, and TNNT3 have been previously shown to be downregulated during tissue expansion ( Ledwon et al, 2020 ). These genes may control the morphology and polarity of the cell during tissue expansion.…”

“…A recent study showed that glycolysis responds to architectural features of the actomyosin cytoskeleton, which couple cancer cell metabolism to the mechanical properties of the surrounding tissue ( Park et al, 2020 ). Another transcriptomic analysis related to mechanical stretch-induced skin changes in pigs showed the involvement of an expansive list of metabolic processes, including glycolysis ( Ledwon et al, 2020 ). However, in this study, the results of KEGG analysis did not display a significant difference in glycolysis.…”

“…Biological signals then affect gene expression by initiating signaling cascades, which ultimately leads to skin regeneration. Several studies have demonstrated the occurrence of molecular alterations and related biological processes during tissue expansion ( Aragona et al, 2020 ; Ledwon et al, 2020 ). However, the biological processes and molecular mechanisms involved in mechanically induced skin regeneration have not been well elucidated.…”

“…Skin regeneration associated with tissue expansion is a biological process accompanied by gene transcriptional changes ( Ledwon et al, 2020 ; Park et al, 2020 ). Physiologically, transcriptional regulation and molecular signaling involve precise gene activation and suppression ( Tajik et al, 2016 ).…”