scholarly journals Adenomyosis: Mechanisms and Pathogenesis

2020 ◽  
Vol 38 (02/03) ◽  
pp. 129-143 ◽  
Author(s):  
Junyu Zhai ◽  
Silvia Vannuccini ◽  
Felice Petraglia ◽  
Linda C. Giudice
Keyword(s):  
Stem Cells ◽  
Smooth Muscle ◽  
Targeted Therapies ◽  
Pituitary Hormones ◽  
Uterine Wall ◽  
Serosal Side ◽  
Stromal Fibroblasts ◽  
Endometrial Cells ◽  
Underlying Mechanisms ◽  
Endometrial Epithelial Cells

AbstractAdenomyosis is a common disorder of the uterus, and is associated with an enlarged uterus, heavy menstrual bleeding (HMB), pelvic pain, and infertility. It is characterized by endometrial epithelial cells and stromal fibroblasts abnormally found in the myometrium where they elicit hyperplasia and hypertrophy of surrounding smooth muscle cells. While both the mechanistic processes and the pathogenesis of adenomyosis are uncertain, several theories have been put forward addressing how this disease develops. These include intrinsic or induced (1) microtrauma of the endometrial–myometrial interface; (2) enhanced invasion of endometrium into myometrium; (3) metaplasia of stem cells in myometrium; (4) infiltration of endometrial cells in retrograde menstrual effluent into the uterine wall from the serosal side; (5) induction of adenomyotic lesions by aberrant local steroid and pituitary hormones; and (6) abnormal uterine development in response to genetic and epigenetic modifications. Dysmenorrhea, HMB, and infertility are likely results of inflammation, neurogenesis, angiogenesis, and contractile abnormalities in the endometrial and myometrial components. Elucidating mechanisms underlying the pathogenesis of adenomyosis raise possibilities to develop targeted therapies to ameliorate symptoms beyond the current agents that are largely ineffective. Herein, we address these possible etiologies and data that support underlying mechanisms.

scholarly journals Altered Differentiation of Endometrial Mesenchymal Stromal Fibroblasts Is Associated With Endometriosis Susceptibility

2021 ◽  
Author(s):  
Brett McKinnon ◽  
Samuel Lukowski ◽  
Sally Mortlock ◽  
Joanna Crawford ◽  
Rebecca Johnston ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cellular Differentiation ◽  
Disease Susceptibility ◽  
Mesenchymal Cell ◽  
Stromal Fibroblast ◽  
Stromal Fibroblasts ◽  
Endometrial Cells ◽  
Growth Profiles

Abstract Cellular development is tightly regulated as mature cells with aberrant functions may initiate pathogenic processes. The endometrium is a highly regenerative tissue, shedding and regenerating each month. Endometrial stromal fibroblasts are regenerated each cycle from mesenchymal stem cells and play a pivotal role in endometriosis, a disease characterised by endometrial cells that grow outside the uterus. Why the cells of some women are more capable of developing into endometriosis lesions is not clear. Using isolated, purified and cultured endometrial cells of mesenchymal origin from 19 women with (n = 10) and without (n = 9) endometriosis we analysed the transcriptome of 33,758 individual cells and compared these to clinical characteristics and in vitro growth profiles. We show purified mesenchymal cell cultures include a mix of mesenchymal stem cells and two endometrial stromal fibroblast subtypes with distinct transcriptomic signatures indicative of varied progression through the differentiation processes. The fibroblast subgroup characterised by incomplete differentiation was predominantly (81%) derived from women with endometriosis and exhibited an altered in vitro growth profile. These results uncover an inherent difference in endometrial cells of women with endometriosis and highlight the relevance of cellular differentiation and its potential to contribute to disease susceptibility.

scholarly journals Human-Induced Pluripotent Stem-Cell-Derived Smooth Muscle Cells Increase Angiogenesis to Treat Hindlimb Ischemia

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 792
Author(s):  
Xixiang Gao ◽  
Mingjie Gao ◽  
Jolanta Gorecka ◽  
John Langford ◽  
Jia Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Smooth Muscle ◽  
Stem Cell ◽  
Smooth Muscle Cells ◽  
Functional Outcomes ◽  
Ethical Issues ◽  
Muscle Cells ◽  
Doppler Imaging ◽  
Hindlimb Ischemia ◽  
Induced Pluripotent

Induced pluripotent stem cells (iPSC) represent an innovative, somatic cell-derived, easily obtained and renewable stem cell source without considerable ethical issues. iPSC and their derived cells may have enhanced therapeutic and translational potential compared with other stem cells. We previously showed that human iPSC-derived smooth muscle cells (hiPSC-SMC) promote angiogenesis and wound healing. Accordingly, we hypothesized that hiPSC-SMC may be a novel treatment for human patients with chronic limb-threatening ischemia who have no standard options for therapy. We determined the angiogenic potential of hiPSC-SMC in a murine hindlimb ischemia model. hiPSC-SMC were injected intramuscularly into nude mice after creation of hindlimb ischemia. Functional outcomes and perfusion were measured using standardized scores, laser Doppler imaging, microCT, histology and immunofluorescence. Functional outcomes and blood flow were improved in hiPSC-SMC-treated mice compared with controls (Tarlov score, p < 0.05; Faber score, p < 0.05; flow, p = 0.054). hiPSC-SMC-treated mice showed fewer gastrocnemius fibers (p < 0.0001), increased fiber area (p < 0.0001), and enhanced capillary density (p < 0.01); microCT showed more arterioles (<96 μm). hiPSC-SMC treatment was associated with fewer numbers of macrophages, decreased numbers of M1-type (p < 0.05) and increased numbers of M2-type macrophages (p < 0.0001). Vascular endothelial growth factor (VEGF) expression in ischemic limbs was significantly elevated with hiPSC-SMC treatment (p < 0.05), and inhibition of VEGFR-2 with SU5416 was associated with fewer capillaries in hiPSC-SMC-treated limbs (p < 0.0001). hiPSC-SMC promote VEGF-mediated angiogenesis, leading to improved hindlimb ischemia. Stem cell therapy using iPSC-derived cells may represent a novel and potentially translatable therapy for limb-threatening ischemia.

scholarly journals MicroRNA-145 regulates the differentiation of human adipose-derived stem cells to smooth muscle cells via targeting Krüppel-like factor 4

2017 ◽  
Vol 15 (6) ◽  
pp. 3787-3795 ◽  
Author(s):  
Kaisaier Aji ◽  
Yun Zhang ◽  
Abudusaimi Aimaiti ◽  
Yujie Wang ◽  
Mulati Rexiati ◽  
...  
Keyword(s):  
Stem Cells ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Adipose Derived Stem Cells

Smooth-Muscle-Like Cells Derived from Human Embryonic Stem Cells Support and Augment Cord-Like Structures In Vitro

2010 ◽  
Vol 6 (2) ◽  
pp. 237-247 ◽  
Author(s):  
Elaine Vo ◽  
Donny Hanjaya-Putra ◽  
Yuanting Zha ◽  
Sravanti Kusuma ◽  
Sharon Gerecht
Keyword(s):  
Stem Cells ◽  
Smooth Muscle ◽  
Embryonic Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Embryonic Stem

scholarly journals Single-cell RNA sequencing of cultured human endometrial CD140b+CD146+ perivascular cells highlights the importance of in vivo microenvironment

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Dandan Cao ◽  
Rachel W. S. Chan ◽  
Ernest H. Y. Ng ◽  
Kristina Gemzell-Danielsson ◽  
William S. B. Yeung
Keyword(s):  
Stem Cells ◽  
Single Cell ◽  
Rna Sequencing ◽  
Marker Gene ◽  
Cellular Heterogeneity ◽  
Stromal Fibroblast ◽  
Perivascular Cells ◽  
Endometrial Cells ◽  
Single Cell Rna Sequencing

Abstract Background Endometrial mesenchymal-like stromal/stem cells (eMSCs) have been proposed as adult stem cells contributing to endometrial regeneration. One set of perivascular markers (CD140b&CD146) has been widely used to enrich eMSCs. Although eMSCs are easily accessible for regenerative medicine and have long been studied, their cellular heterogeneity, relationship to primary counterpart, remains largely unclear. Methods In this study, we applied 10X genomics single-cell RNA sequencing (scRNA-seq) to cultured human CD140b+CD146+ endometrial perivascular cells (ePCs) from menstrual and secretory endometrium. We also analyzed publicly available scRNA-seq data of primary endometrium and performed transcriptome comparison between cultured ePCs and primary ePCs at single-cell level. Results Transcriptomic expression-based clustering revealed limited heterogeneity within cultured menstrual and secretory ePCs. A main subpopulation and a small stress-induced subpopulation were identified in secretory and menstrual ePCs. Cell identity analysis demonstrated the similar cellular composition in secretory and menstrual ePCs. Marker gene expression analysis showed that the main subpopulations identified from cultured secretory and menstrual ePCs simultaneously expressed genes marking mesenchymal stem cell (MSC), perivascular cell, smooth muscle cell, and stromal fibroblast. GO enrichment analysis revealed that genes upregulated in the main subpopulation enriched in actin filament organization, cellular division, etc., while genes upregulated in the small subpopulation enriched in extracellular matrix disassembly, stress response, etc. By comparing subpopulations of cultured ePCs to the publicly available primary endometrial cells, it was found that the main subpopulation identified from cultured ePCs was culture-unique which was unlike primary ePCs or primary endometrial stromal fibroblast cells. Conclusion In summary, these data for the first time provides a single-cell atlas of the cultured human CD140b+CD146+ ePCs. The identification of culture-unique relatively homogenous cell population of CD140b+CD146+ ePCs underscores the importance of in vivo microenvironment in maintaining cellular identity.

Differentiation of adipose tissue-derived stem cells towards vascular smooth muscle cells on modified poly(L-lactide) foils

2021 ◽  
Vol 16 (2) ◽  
pp. 025016
Author(s):  
Martina Travnickova ◽  
Nikola Slepickova Kasalkova ◽  
Antonin Sedlar ◽  
Martin Molitor ◽  
Jana Musilkova ◽  
...  
Keyword(s):  
Stem Cells ◽  
Adipose Tissue ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells

Abstract MP246: Epigenetic Regulation At LRP1 Susceptibility Locus And Characterization Of LRP1 Function In Human Induced Pluripotent Stem Cells Derived Smooth Muscle Cells

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
LU LIU ◽  
Adrien Georges ◽  
Nabila Bouatia-Naji
Keyword(s):  
Stem Cells ◽  
Smooth Muscle ◽  
Coronary Artery ◽  
Smooth Muscle Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Reporter Assay ◽  
Enhancer Activity ◽  
Enhancer Region ◽  
Induced Pluripotent

Introduction: The low-density lipoprotein receptor-related protein 1 (LRP1), an endocytic receptor highly expressed in smooth muscle cells (SMCs), participates in diverse biological processes. A common genetic variant located in LRP1 first intron, rs11172113, was associated with several vascular diseases, including coronary artery disease, migraine and spontaneous coronary artery dissection, as well asd with LRP1 expression in arterial tissues. However, the biological mechanisms through which rs11172113 influence LRP1 function in the context of arterial lesions is not fully understood. Methods: We applied in silico functional annotation to select variants and measured their enhancer activity using luciferase reporter assay in rat primary cells (A7r5). We performed siRNA knockdown of LRP1 and 4 transcription factors (TFs) predicted to interact with rs11172113 in human induced pluripotent stem cells (iPSCs) derived SMCs. We analyzed both contractile (CSMCs) and synthetic (SSMCs) differentiated cells. We edited iPSCs prior to differentiation using CRISPR-Cas9 to generate 100 bp deletion of the enhancer region containing rs11172113. We also created frame-shift indels in exons 2 or 5 of LRP1 in iPSCs to create SMCs knockouts. Results: Seven variants in LRP1 locus co-located with enhancer (histone marks) and open chromatin regions (ATAC-Seq peaks) in SMCs and arterial tissues. Reporter assay in rat SMCs confirmed that rs11172113 belongs to a genomic region showing enhancer activity in vitro . iPSCs with homozygous deletion of rs11172113 enhancer region presented the same pluripotency compared with wild type, and iPSC derived SMCs showed positive expression of specific markers for each phenotype. We found that the deletion of enhancer region decreased the expression of LRP1 in both CSMCs and SSMCs. LRP1 knockdown decreased SSMCs and CSMCs proliferation capacity, but increased cell migration. Knockdown of TFs and iPSCs derived CSMCs and SSMCs with LRP1 knockout are currently under assessment. Conclusions: We confirmed rs11172113 to regulate LRP1 expression in iPSCs derived synthetic and contractile SMCs. Our results support LRP1 effect on SMCs phenotype alteration as a potential mechanism in genetic susceptibility for vascular disease.

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