A recent peer-review article available online from F&S Science reports differential expression of genes and proteins induced by compression force in uterine fibroid cells in cultured spheroids compared to myometrial cells under the same conditions. This paper from the Schutte Laboratory in Cincinnati, Ohio is one that is a must read for scientists currently studying the initiation of uterine fibroids. First, the authors describe an new enhanced method of embedded fibroid cell spheroids for the study of fibroids, and second, the report clearly shows that mechanical force will induce the expression of multiple genes, strongly suggesting that mechanical stimuli could be important in the initiation of fibroid growth.
The scientists developed a method of embedding fibroid and myometrial cell spheroids on agarose in order to cushion them and to provide a distribution of the compressive force. In the study fibroid and myometrial cells were obtained from five subject’s specimens post -surgery. The spheroids were developed over a 7-day-period. The spheroids were them embedded in agarose and 24 hours later they were subjected to 6.4 mm Hg of compression for the subsequent 7 days. Controls with 0 weight were studied for each individual experiment. Following this 7-day compression spheroids were analyzed by histology, proteomics, and RNA seq. Compression of the myometrial spheroids altered the expression of proteins known to be expressed in uterine fibroids. Schutte and colleagues reported alterations in collagens, describing an abundant increase following compression force. They report that 96 clinically relevant differentially expressed genes were not affected by compression. However, 99 differentially expressed genes were enhanced by compression while 150 proteins were only differentially expressed when cells were grown under compression. These findings demonstrate that mechanotransduction has role in both gene and protein expression in the fibroid and myometrial cells of the spheroids. These studies are important in understanding the role of mechanical signaling in fibroid initiation. The study also provides a new model of embedded spheroids of cells in fibroid research.
There are many more experiments to be developed and conducted to prove the role of mechanical force in uterine fibroid development and growth. The authors found that collagen was abundant in the treated cell spheroids. However, there is a pressing need for additional studies on fibroid collagen. The article states that they found a significant increase in collagen type XXIII. Presumably, they evaluated COL23A1, the gene encoded the peptide chains. Collagen Type XXIII is a transmembrane protein and is non-fibrillar collagen. It is expressed on epithelial cell surface and it considered to function in cell-cell contact and adherence. While it was noted in fibroid cells in this study it is critical to remember that the abundant collagen found in uterine fibroids is primarily Type I and Type III collagen. These are interstitial collagens. Their genes undergo translation and transcription to produce propeptide chains which undergo a complex processing to then become mature crosslinked collagen. This processing occurs both intracellularly and extracellularly. While the intercellular processing will occur in approximately 20 minutes to hours prior to being secreted into the extracellular space, the final processing which includes propeptide cleavage and fiber assembly to form trophocollagen takes 24 hours . Cross-linking and maturation of Collagen Type I and III takes months. It is this mature interstitial collagen which provides the mechanical force and the necessary mechanical signaling in vivo to develop fibroids. Thus, the experiments described in this article where not continued long enough to test the hypothesis of mechanical transduction leading to fibroid initiation and growth. The scientists attribute the relative decrease in collagen protein expression compared to gene expression in the study to an increase in MMP1. MMP1 only cleaves interstitial collagens at one specific bond and produces a degradation product that is 1/4 and 3/4 of the original molecule. The role of MMP1 in cells is to activate an number of enzymes and it has multiple substrates in addition to interstitial collagens. Its increase in fibrotic tissue is documented but the mechanisms that cause this association are complex. Thus, further studies are warranted.
Finally, the spheroids studies were not carried out in a long enough timeframe to determine if the spheroid cells developed mutations in the MED-12 gene, a gene that is found in uterine fibroids. This is a factor in the study of HMGA2 gene, another gene that is found to be differentially expressed in fibroids. Hopefully, the Schutte lab and other labs working in fibroid biology will carry out the necessary studies to provide further knowledge to completely understand the role of mechanical signaling in fibroid initiation and growth. Much has been learned from this article, especially the fact that mechanical signaling does cause changes in gene expression.
Reference:
Nietupski. CA, Sax MR, Dean R, Zupan AM, Hurley EG, Schutte SC, Compressive Force Induces Differential Gene and Protein Expression in Uterine Fibroids, F&S Science (2025), doi: https://doi.org/10.1016/j.xfss.2025.07.004.