Common fibroid-associated genes are differentially expressed in phenotypically dissimilar cell populations isolated from within human fibroids and myometrium

Holdsworth-Carson, Sarah J.; Zaitseva, Marina; Girling, Jane E.; Vollenhoven, Beverley; Rogers, Peter A. W.

doi:10.1530/rep-13-0580

Cited by 11 publications

(8 citation statements)

References 58 publications

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“…We detected ADM in patientmatched myometrial and leiomyoma tissue sections, although the expression varied (data not shown). Our results were consistent with reported discordant ADM expression found in other studies (58). Analysis of cells grown in culture showed a statistically significant decrease in ADM expression in hypoxic myometrium at 6 hours, and a >1.5-fold increase during hypoxia, when compared with normoxic myometrium (Fig.…”

Section: Discussionsupporting

confidence: 93%

Three-dimensional human leiomyoma xenografts induce angiogenesis by inducing hypoxia inducible factor-1 alpha

et al. 2021

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Objective: To characterize the method by which angiogenesis occurred in three-dimensional (3D) leiomyoma xenografts, and to assess the impact of hypoxia on two-dimensional (2D) and 3D myometrial and leiomyoma cells and leiomyoma xenografts in vivo. Design: Laboratory study. Setting: Academic research. Patient(s): Cell cultures from patient-matched myometrial and leiomyoma tissues. Intervention(s): In vivo 3D leiomyoma xenografts from ovariectomized mice treated with gonadal hormones; myometrial and leiomyoma cells in 2D and 3D growth formats exposed to 1% oxygen. Main Outcome Measure(s): Protein expression. Result(s): Blood vessels in the xenograft estradiol group are identified with anti-mouse/anti-rat CD31/PECAM-1 antibody. Hormonestimulated 3D leiomyoma xenografts stain positively for adrenomedullin (ADM). Myometrial cells exposed to 1% oxygen demonstrated an increase in hypoxia-inducible factor (HIF)-1a at 6 hours and a marked increase at 24 hours. Under normoxic conditions, leiomyoma cells at 6 hours show increased expression of HIF-1a, which is further increased at 24 hours. Leiomyoma cells under hypoxia demonstrated a 1.14-fold decrease in HIF-1a expression at 6 hours and no change at 24 hours. Hypoxic myometrium decreased the proangiogenic protein ADM expression at 6 hours and showed a >1.5-fold increase at 24 hours. Normoxic leiomyoma decrease ADM at 24 hours and showed a >1.5-fold increase at 24 hours of hypoxia. Conclusion(s): Hypoxia-induced HIF-1a expression facilitates angiogenesis in 3D xenografts in vivo by increasing the expression of the proangiogenic protein ADM. Angiogenesis contributes to the viability and extended survival of these xenografts. Furthermore, 2D myometrial and leiomyoma cells increase HIF-1a and ADM expression in vitro under hypoxic conditions. (Fertil Steril Sci Ò 2021;2: 219-27. Ó2020 by American Society for Reproductive Medicine.

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Section: Discussionsupporting

confidence: 93%

Three-dimensional human leiomyoma xenografts induce angiogenesis by inducing hypoxia inducible factor-1 alpha

et al. 2021

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“…Recent work by us and others have established that the cellular phenotypes of uterine fibroids are heterogeneous (Koumas et al 2001, Moore et al 2010, Zhao & Rogers 2013, Holdsworth-Carson et al 2014a. Studying the different cellular populations present within fibroids confirms the phenotypic plasticity of these cells and the dynamic nature of commonly used cell markers.…”

Section: Introductionmentioning

confidence: 66%

“…Myometrium from post-menopausal women exhibited increased ALDH1A1 expression. ALDH1A1 belongs to the retinoic acid (RA) pathway, which is known to be altered in fibroids (Catherino & Malik 2007, Zaitseva et al 2007, Holdsworth-Carson et al 2014a. Some RA pathway components are responsive to oestrogen, including cellular retinoic acid-binding protein 2 (CRABP2) (Li & Ong 2003), retinoid X receptor alpha (RXRα) and peroxisome proliferator-activated receptor gamma (PPARγ) (Tsibris et al 1999).…”

Section: Discussionmentioning

confidence: 99%

Differences in the cellular composition of small versus large uterine fibroids

Holdsworth-Carson¹,

Zhao²,

Cann³

et al. 2016

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Uterine fibroids are clonally derived from a single cell; however, despite being monoclonal, the cellular phenotypes that make up uterine fibroids are heterogeneous consisting of predominantly smooth muscle cells (SMC) and fibroblasts. This raises the question as to when clonal cell differentiation occurs during fibroid development, and does this information provide clues about possible mechanisms regulating the growth process that leads to fibroids of symptom-causing size? This study investigated the differences in the cellular composition of fibroids by immunohistochemistry (IHC). A tissue microarray (n = 21 hysterectomy cases) was used for the investigation of large uterine fibroids and normal myometrium. An investigation of small fibroids (≤ 5mm) used a separate group of samples (n = 7 hysterectomy cases, total of n = 17 fibroids). A panel of cell phenotypic markers was selected based on our previous in situ investigations and included aldehyde dehydrogenase 1 (ALDH1A1) and vimentin for different fibroblast sub-populations, smooth muscle actin (SMA) as a marker for SMCs, CD31 for endothelial cells and CD45 for leucocytes. Proliferating cell nuclear antigen (PCNA) was also studied to identify proliferating cells. The cellular composition of small fibroids differs significantly from large fibroids. Small fibroids are more cellular (increased cells/mm(2)) than large fibroids, have more blood vessels and also have a higher ratio of SMC to fibroblasts than large fibroids. Large fibroids have more cell proliferation (measured by PCNA) and fewer leucocytes (measured by CD45) than adjacent myometrium, whereas small fibroids are less proliferative and have similar number of leucocytes to myometrium. Different cellular composition between fibroids of different sizes may provide important clues as to the mechanisms that drive fibroid growth.

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“…Uterine leiomyomas are thought to originate from SMC in myometrium. However, recent studies have reported presence of fibroblasts and endothelial cells in uterine leiomyomas in addition to SMC populations 10,12 , thus suggesting presence of cellular heterogeneity in leiomyomas. We applied single cell RNA sequencing technique to create a cell atlas for the normal myometrium and the leiomyomas.…”

Section: Discussionmentioning

confidence: 99%

“…Leiomyomas are considered monoclonal tumors of smooth muscle cell in uterus 11 . However, recent histological and flow cytometry studies have shown the presence of smooth muscle cells, fibroblasts, endothelial cells and immune cells in leiomyomas 12 . How these cells contribute to the leiomyoma formation and the molecular salient characteristics of the cellular heterogeneity in leiomyomas remain undetermined.…”

Section: Introductionmentioning

confidence: 99%

Single Cell atlas of uterine myometrium and leiomyomas reveals diverse and novel cell types of non-monoclonal origin

Goad

Rudolph

Wei

et al. 2020

Preprint

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Uterine leiomyomas are the most common tumors of the female reproductive tract with significant morbidity that includes excessive bleeding, infertility and pregnancy complications. The origin and cellular composition of leiomyomas is controversial, yet very important in better understanding the pathogenesis of these tumors. We applied single-cell RNA sequencing to better understand cellular heterogeneity of uterine leiomyomas and normal myometrium at the molecular level. Our data reveal previously unknown heterogeneity in the smooth muscle cells, fibroblast cells, and endothelial cells of normal myometrium and leiomyomas. We discovered a novel lymphatic endothelial cell population in uterine leiomyomas and that the immune as well as transcriptional profile of leiomyomas is MED12 genotype-dependent. Moreover, we show that leiomyoma cell moiety is not monoclonal in nature. Our work describes unprecedented single cell resolution of normal uterine myometrium and leiomyoma tumors and provides insight into tumor specific hormone responsiveness and extracellular matrix accumulation.

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Common fibroid-associated genes are differentially expressed in phenotypically dissimilar cell populations isolated from within human fibroids and myometrium

Cited by 11 publications

References 58 publications

Three-dimensional human leiomyoma xenografts induce angiogenesis by inducing hypoxia inducible factor-1 alpha

Three-dimensional human leiomyoma xenografts induce angiogenesis by inducing hypoxia inducible factor-1 alpha

Differences in the cellular composition of small versus large uterine fibroids

Single Cell atlas of uterine myometrium and leiomyomas reveals diverse and novel cell types of non-monoclonal origin

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