Evidence of biomechanical and collagen heterogeneity in uterine fibroids

Abstract

Objective Uterine fibroids (leiomyomas) are common benign tumors of the myometrium but their molecular pathobiology remains elusive. These stiff and often large tumors contain abundant extracellular matrix (ECM), including large amounts of collagen, and can lead to significant morbidities. After observing structural multiformities of uterine fibroids, we aimed to explore this heterogeneity by focusing on collagen and tissue stiffness. Methods For 19 fibroids, ranging in size from 3 to 11 centimeters, from eight women we documented gross appearance and evaluated collagen content by Masson trichrome staining. Collagen types were determined in additional samples by serial extraction and gel electrophoresis. Biomechanical stiffness was evaluated by rheometry. Results Fibroid slices displayed different gross morphology and some fibroids had characteristics of two or more patterns: classical whorled (n = 8); nodular (n = 9); interweaving trabecular (n = 9); other (n = 1). All examined fibroids contained at least 37% collagen. Tested samples included type I, III, and V collagen of different proportions. Fibroid stiffness was not correlated with the overall collagen content (correlation coefficient 0.22). Neither stiffness nor collagen content was correlated with fibroid size. Stiffness among fibroids ranged from 3028 to 14180 Pa (CV 36.7%; p<0.001, one-way ANOVA). Stiffness within individual fibroids was also not uniform and variability ranged from CV 1.6 to 42.9%. Conclusions The observed heterogeneity in structure, collagen content, and stiffness highlights that fibroid regions differ in architectural status. These differences might be associated with variations in local pressure, biomechanical signaling, and altered growth. We conclude the design of all fibroid studies should account for such heterogeneity because samples from different regions have different characteristics. Our understanding of fibroid pathophysiology will greatly increase through the investigation of the complexity of the chemical and biochemical signaling in fibroid development, the correlation of collagen content and mechanical properties in uterine fibroids, and the mechanical forces involved in fibroid development as affected by the various components of the ECM.

Advanced 3D Imaging of Uterine Leiomyoma’s Morphology by Propagation-based Phase-Contrast Microtomography

“…With the same indication, evidence of biomechanical and biochemical heterogeneity in uterine fibroids has just been reported. The authors observed heterogeneity in structure, collagen content, and stiffness highlighting that fibroid regions differ in biochemical status and they suggest that these differences might be associated with variations in local pressure, biomechanical signaling, and altered growth 68 .…”

“…For instance, collagen density distributions in human knee ligaments were documented to quantify differences in density within and between these ligaments 69 . Very recently, heterogeneity in structure, collagen content, and stiffness in uterine fibroids was reported 68 . Thus, it is interesting to evaluate if this heterogeneity is expressed also in terms of density distributions, as it was shown in human knee ligaments.…”

Perinatal complications of pregnancies complicated by uterine fibroids

“…Sastoje se od glatkih mišićnih ćelija, fibroblasta i ekstracelularnog matriksa [3]. Obilna količina ekstracelularnog matriksa, koju grade glikozaminoglikani i gusto zbijeni intersticijumski kolagen, čini tkivo mioma dva do četiri puta čvršćim od miometrijuma [4]. Ovi tumori su jasno ograničeni od okolnog tkiva pseudokapsulom, koja nastaje kao rezultat kompresije miometrijuma njihovim progresivnim rastom.…”

“…They consist of smooth muscle cells, fibroblasts and extracellular matrix [3]. A profuse amount of extracellular matrix, which is made up of glycosaminoglycans and densely packed interstitial collagen, makes the myoma tissue two to four times firmer than the myometrium [4]. These tumors are clearly delineated by a pseudocapsule which separates them from the surrounding tissue.…”

Uterine fibroids and preterm birth risk: A systematic review and meta‐analysis

“…These properties are related to the local pressure, biochemical signals and altered growth. 2 Many fibroids are discovered incidentally in asymptomatic women upon clinical or ultrasonographic examination. 3 Age and ethnicity are risk factors for UF development and growth, and they may be present in up to 70% of perimenopausal women.…”