416. A xenotransplantation model for investigating the role of human endometrial stem/progenitor cells in endometriosis

2008 ◽  
Vol 20 (9) ◽  
pp. 96
Author(s):  
C. E. Gargett ◽  
T. Kaitu'u-Lino ◽  
R. W. S. Chan
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Smooth Muscle Actin ◽  
Human Reproduction ◽  
Endometrial Cells ◽  
Endometrial Epithelium ◽  
Immunocompromised Mice ◽  
Ectopic Endometriosis ◽  
Weekly Cycles

Endometriosis is a major cause of infertility in women. Recent evidence suggests that stem/progenitor cells are present in human endometrium which may be responsible for its remarkable regenerative capacity.1 In mouse endometrium, candidate epithelial and stromal stem/progenitor cells have been identified as label retaining cells (LRC).2 We hypothesised that endometrial stem/progenitor cells gain access to the peritoneal cavity in menstrual debris where they establish ectopic endometriosis lesions in women who develop endometriosis3. Our aim was to identify LRC in human endometrial tissues transplanted into an ectopic site in immunocompromised mice. Endometrium was dissected into pieces (1x1 mm × depth of endometrium) from hysterectomy tissues from ovulating women (n = 7) and transplanted beneath the kidney capsule of ovariectomised NOD/SCID mice. One week later, mice were administered a single 100 ng oestradiol valerate (E2) injection and 50 ug/g BrdU (6 ip injections over 3 days) to label proliferating endometrial cells with BrdU. E2 injections were given fortnightly to induce weekly cycles of endometrial growth and regression and to chase out the BrdU. Mice were sacrificed after 6–12 weeks chase and the explants examined for LRC and other markers by immunofluorescence. Endometrial explants underwent major remodelling during the BrdU pulse-chase, and cells in both glands and stroma underwent proliferation (PCNA+). Rare LRC were identified in the human endometrial epithelium and stroma. Epithelial LRC were ER-α negative while some stromal LRC were ER-α+ by confocal microscopy. Immunostaining of the LRC for ER-β, α-smooth muscle actin and human endometrial stromal stem/progenitor cell markers (CD146, PDGFR-β)4 will further characterise these candidate stem/progenitor cell populations in ectopic endometrium. This preliminary study suggests that combining the LRC technique with xenotransplantation of human endometrial tissue into a well vascularised ectopic site may provide a novel model for investigating the role of endometrial epithelial and stromal stem/progenitor cells in the pathogenesis of endometriosis. (1) Chan RWS et al. (2004). Biology of Reproduction. 70:1738–1750 (2) Chan RWS, Gargett CE (2006). Stem Cells 24:1529–1538 (3) Gargett CE (2007) Human Reproduction Update 13:87–101 (4) Schwab KE, Gargett CE (2007) Human Reproduction 22:2903–2911

O-065 The naughty cells of the endometriumxx

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
C Gargett
Keyword(s):  
Stem Cells ◽  
Progenitor Cells ◽  
Epithelial Mesenchymal Transition ◽  
Lineage Tracing ◽  
Gene Profiling ◽  
Human Reproduction ◽  
Perivascular Cells ◽  
Mesenchymal Transition ◽  
Endometrial Cells ◽  
Epithelial Progenitor Cells

Abstract Stem/progenitor cells are the naughty cells of the endometrium! The term “naughty” has a number of connotations, one being immaturity which I will apply to the rare stem/progenitor cell populations hiding in the endometrium, where they have eluded scientists for so long. Despite their rarity, these immature cells have the capability of growing up and differentiating into the functional cells of the endometrium, producing their progenies in the process. The self-willed human endometrial epithelial progenitor cells (eEPC) and mesenchymal stem cells (eMSC) first revealed themselves through their clonogenic activity, shunning their mates and setting up clones of cells on their own. Their risqué production of identical copies of themselves ensures their continuity, much to the chagrin of their mature counterparts. They are sneaky and can produce large numbers of mature progeny, but rarely proliferate themselves preferring to take life easy and do little. They also spit out viability dyes (Hoechst) at a greater rate than mature endometrial cells to become Side Population (SP) cells. A number of approaches have been used to tame these naughty endometrial stem/progenitors. In order to determine the identity and location of these elusive cells, specific markers had to be found. The immature endometrial epithelial progenitor cells play tricks with the specific markers they express. For example, clonogenic eEPC are N-cadherin+, an epithelial mesenchymal transition marker, found by unbiassed gene profiling, revealed their hiding place in the bases of glands deep in the endometrial basalis. Similarly, SSEA-1+ basalis epithelial progenitors pirated their marker from mature neutrophils and differentiating human pluripotent stem cells. In mice the stem/progenitor cells like to play chase, with lineage tracing of individual genetically marked cells revealing their location in the intersection zone of the glands and luminal epithelium, and also in the gland bases (Axin2+ and Lgr5+). The identity of eMSCs has also been determined by discovery of specific markers, but even here the eMSC play games in human endometrium where sometimes they are pericytes (CD140b and CD146 double positive cells), sometimes perivascular cells (SUSD2+) and sometimes CD34+ cells in the adventitia of blood vessels. They are also adventitial perivascular cells in ovine endometrium, but this time they are CD271+. Mature endometrial stromal cell progeny are also naughty, often pretending to be eMSC, particularly when shed into menstrual fluid, confusing many of their status. Adding further to their misbehaviour, they express the same official MSC surface markers. To get even immature endometrial MSC strike back, claiming immunomodulatory properties in attempt to upstage their mature stromal progeny, also endowed with these properties. Finally, other endometrial cells such as macrophages may also be naughty as their mischievousness in evading detection can trick us to consider them as stem cells from the bone marrow, masquerading as endometrial epithelial or stromal cells. Naughty implies behaving badly and I will show data suggesting that stem/progenitor cells may escape the endometrium to cause a nasty disease, endometriosis. They may also become wayward and unruly, invading the myometrium to form adenomyosis. Some naughty epithelial progenitors defiantly pick up mutations to become cancer stem cells and initiate endometrial cancer. They may also malfunction because they do not obey estrogen signalling instructions, failing to proliferate and causing thin unresponsive endometrium. In their naughtiness, they may run away or get totally lost, thereby resulting in Asherman’s syndrome. Therefore, for numerous reasons, stem/progenitor cells are the naughty cells of the endometrium. © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: [email protected].

scholarly journals Notch signaling represses cone photoreceptor formation through the regulation of retinal progenitor cell states

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Xueqing Chen ◽  
Mark M. Emerson
Keyword(s):  
Notch Signaling ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Regulatory Elements ◽  
Primary Role ◽  
Cone Photoreceptor ◽  
Cone Photoreceptors ◽  
Retinal Progenitor Cells ◽  
Retinal Progenitor

AbstractNotch signaling is required to repress the formation of vertebrate cone photoreceptors and to maintain the proliferative potential of multipotent retinal progenitor cells. However, the mechanism by which Notch signaling controls these processes is unknown. Recently, restricted retinal progenitor cells with limited proliferation capacity and that preferentially generate cone photoreceptors have been identified. Thus, there are several potential steps during cone genesis that Notch signaling could act. Here we use cell type specific cis-regulatory elements to localize the primary role of Notch signaling in cone genesis to the formation of restricted retinal progenitor cells from multipotent retinal progenitor cells. Localized inhibition of Notch signaling in restricted progenitor cells does not alter the number of cones derived from these cells. Cell cycle promotion is not a primary effect of Notch signaling but an indirect effect on progenitor cell state transitions that leads to depletion of the multipotent progenitor cell population. Taken together, this suggests that the role of Notch signaling in cone photoreceptor formation and proliferation are both mediated by a localized function of Notch in multipotent retinal progenitor cells to repress the formation of restricted progenitor cells.

scholarly journals Hepatic Progenitor Cells Promote the Repair of Schistosomiasis Liver Injury Through Inhibiting IL-33 Secretion 

2021 ◽  
Author(s):  
Beibei Zhang ◽  
Xiaoying Wu ◽  
Jing Li ◽  
An Ning ◽  
Bo Zhang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Normal Liver ◽  
Protective Role ◽  
Hepatic Progenitor Cells ◽  
Mice Model ◽  
Blocking Antibody

Abstract Background: Hepatic schistosomiasis, a chronic liver injury induced by long-term Schistosoma japonicum (S. japonicum) infection, is characterized by egg granulomas and fibrotic pathology. Hepatic progenitor cells (HPCs), which are nearly absent and quiescent in normal liver, play vital roles in chronic and severe liver injury. But their role in the progression of liver injury during infection remained unknown.Methods: In this study, the hepatic egg granulomas, fibrosis and proliferation of HPCs were analyzed in S. japonicum infection mice model at different infection stages. For validating the role of HPCs in hepatic injury, TNF­related weak inducer of apoptosis (TWEAK) and TWEAK blocking antibody were used to manipulate the proliferation of HPCs. Histologic pathology and the expression of IL-33 were examined. Results: We found that the proliferation of HPCs paralleled with inflammatory granulomas and fibrosis formation. Promoting HPCs expansion promote the liver regeneration and inhibit the hepatocytes injury, the inflammatory eggs granulomas and the deposition of fibrotic collagen. Interestingly, the expression of IL-33 decreased when HPCs were manipulated to proliferate. Thus, IL-33 might be involved in the liver repair dominated by HPCs. Conclusions: Collectively, our data uncovered a protective role of HPCs in hepatic schistosomiasis in an IL-33 related manner, which might provide a promising progenitor cell therapy for hepatic schistosomiasis.

Role of the Inferior Alveolar Nerve in Rodent Lower Incisor Stem Cells

2018 ◽  
Vol 97 (8) ◽  
pp. 954-961 ◽  
Author(s):  
S. Hayano ◽  
Y. Fukui ◽  
N. Kawanabe ◽  
K. Kono ◽  
M. Nakamura ◽  
...  
Keyword(s):  
Stem Cells ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Tooth Development ◽  
Inferior Alveolar Nerve ◽  
Sensory Nerve ◽  
Cell Homeostasis ◽  
Lower Incisor ◽  
Cell Ratio

In developing teeth, the sequential and reciprocal interactions between epithelial and mesenchymal tissues promote stem/progenitor cell differentiation. However, the origin of the stem/progenitor cells has been the subject of considerable debate. According to recent studies, mesenchymal stem cells originate from periarterial cells and are regulated by neurons in various organs. The present study examined the role of innervation in tooth development and rodent incisor stem/progenitor cell homeostasis. Rodent incisors continuously grow throughout their lives, and the lower incisors are innervated by the inferior alveolar nerve (IAN). In this study, we resected the IAN in adult rats, and the intact contralateral side served as a nonsurgical control. Sham control rats received the same treatment as the resected rats, except for the resection process. The extent of incisor eruption was measured, and both mesenchymal and epithelial stem/progenitor cells were visualized and compared between the IAN-resected and sham-operated groups. One week after surgery, the IAN-resected incisors exhibited a chalky consistency, and the eruption rate was decreased. Micro–computed tomography and histological analyses performed 4 wk after surgery revealed osteodentin formation, disorganized ameloblast layers, and reduced enamel thickness in the IAN-resected incisors. Immunohistochemical analysis revealed a reduction in the CD90- and LRIG1-positive mesenchymal cell ratio in the IAN-resected incisors. However, the p40-positive epithelial stem/progenitor cell ratio was comparable between the 2 groups. Thus, mesenchymal stem/progenitor cell homeostasis is more related to IAN innervation than to epithelial stem/progenitor cells. Furthermore, sensory nerve innervation influences subsequent incisor growth and formation.

Parallel Transcriptional Analysis of Multiple Stem and Progenitor Populations Identifies Novel Commonly Dysregulated and Functionally Relevant Targets in AML

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1875-1875
Author(s):  
Laura Barreyro ◽  
Britta Will ◽  
Boris Bartholdy ◽  
Li Zhou ◽  
Tihomira I Todorova ◽  
...  
Keyword(s):  
Stem Cells ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Normal Karyotype ◽  
Transcriptional Analysis ◽  
Hematopoietic Stem ◽  
Monosomy 7 ◽  
Expression Levels

Abstract Abstract 1875 Recent experimental evidence suggests that acute myeloid leukemia (AML) originates from hematopoietic stem and progenitor cells (HSPC) following the acquisition of multiple genetic or epigenetic changes that initially give rise to pre-leukemic HSPC (pre-LSC) and then to fully transformed leukemia stem cells (LSC). Relapse continues to be the major cause of death in most subtypes of AML, suggesting that current therapies are largely ineffective in eliminating LSC and pre-LSC. Cellular heterogeneity and the recent observation that LSC are contained within different phenotypic cellular compartments are challenges for the identification of pathways contributing to the initiation and maintenance of AML. To address these challenges we employed a novel strategy of parallel transcriptional analysis of multiple phenotypic HSPC populations from individuals with AML with normal karyotype (N=5), -7/7q- (N=6) and complex karyotype (N=5), including long-term HSC, short-term HSC, and granulocyte-monocyte progenitors (GMP), and comparison to corresponding cell populations from age-matched healthy controls (HC) (N=6). Specifically, we sorted Lin−/CD34+/CD38−/CD90+ (LT-HSC), Lin−/CD34+/CD38−/CD90− (ST-HSC), and Lin−/CD34+/CD38+/CD123+/CD45RA+ (GMP), and hybridized RNA to Affymetrix GeneST 1.0 expression arrays. Differential gene expression was determined within each compartment by direct comparison of AML LT-HSC vs. HC LT-HSC, AML ST-HSC vs. HC ST-HSC, and AML GMP vs. HC GMP. Subsequent intersection of all differentially expressed genes revealed that only a relatively small number of 6 to 11 genes were consistently dysregulated in all examined leukemic stem and progenitor cell compartments. Interleukin 1 receptor accessory protein (IL1RAP) was one of the most significantly upregulated genes in LT-HSC, ST-HSC, and GMP in all examined subtypes of AML. IL1RAP is a transmembrane protein required for signaling through several receptors of the IL1 family, including IL-1R1 and ST2. We detected significant overexpression of IL1RAP protein on HSC and progenitor cells of AML patients. Interestingly, CD34+/Lin+ precursor cells showed only a marginal increase of IL1RAP at the protein level in AML, underscoring the importance of purifying HSPC with stringent lineage depletion. We performed fluorescence in situ hybridization in sorted IL1RAP+ and IL1RAP− cells from -7 AML. We observed that the -7 clone was restricted to IL1RAP+ cells, while IL1RAP- cells did not display monosomy 7, demonstrating that IL1RAP overexpression is a distinguishing feature of the cells of the -7 clone. Patients with normal karyotype AML showed a wider range of IL1RAP expression levels; some were as high as in -7 AML and others were as low as in HC. We asked whether IL1RAP expression levels were associated with known clinical or molecular parameters. We analyzed two published datasets of patients with normal karyotype AML (Metzeler, Blood. 2008;112:4193–4201; Tomasson, Blood. 2008;111:4797–4808). Patients with high IL1RAP levels showed inferior overall survival than patients with lower IL1RAP (p=2.2×10−7; median survival: 7.82 mo. for IL1RAP high, 20 mo. for IL1RAP low). Multivariate analysis using a Cox regression model showed that high IL1RAP status was an independent prognostic factor (p=0.002), and even stronger than FLT3 mutation status (p=0.006). In addition, we analyzed data from 183 patients with MDS and found IL1RAP expression to be specifically elevated in cases with RAEB-2, suggesting a role of IL1RAP in MDS and in the progression to AML. Downregulation of IL1RAP protein expression in 4 AML cell lines (THP1, OCI-AML3, HL60, HEL) led to a significant 45–98% decrease in clonogenic growth and increased apoptosis in vitro. To assess the effects of IL1RAP downregulation in vivo, we performed xenotransplants into immunodeficient NOD/SCID/IL2Rg-null mice. THP-1 AML cells showed a 92% reduced proliferation and infiltration of hematopoietic organs upon IL1RAP knockdown in comparison to a non-silencing control in vivo. Genetic studies to assess the role of IL1RAP in the initiation and maintenance of AML in an IL1RAP−/− mouse model are currently ongoing. In summary, our study provides a map of consistently dysregulated transcripts across multiple fractionated stem and progenitor cell types from patients with AML, and identifies IL1RAP as a putative new therapeutic and prognostic target in stem cells in AML and MDS. Disclosures: No relevant conflicts of interest to declare.

The role of the renin–angiotensin–aldosterone system in cardiovascular progenitor cell function

2009 ◽  
Vol 116 (4) ◽  
pp. 301-314 ◽  
Author(s):  
Cheng Qian ◽  
Regien G. Schoemaker ◽  
Wiek H. van Gilst ◽  
Anton J. M. Roks
Keyword(s):  
Myocardial Infarction ◽  
Angiotensin Ii ◽  
Progenitor Cells ◽  
Endothelial Progenitor Cells ◽  
Progenitor Cell ◽  
Cell Function ◽  
Converting Enzyme ◽  
Endothelial Progenitor

Intervention in the RAAS (renin–angiotensin–aldosterone system) is one of the leading pharmacotherapeutic strategies, among others, used for the treatment of cardiovascular disease to improve the prognosis after myocardial infarction and to reduce hypertension. Recently, regenerative progenitor cell therapy has emerged as a possible alternative for pharmacotherapy in patients after myocardial infarction or ischaemic events elsewhere, e.g. in the limbs. Angiogenic cell therapy to restore the vascular bed in ischaemic tissues is currently being tested in a multitude of clinical studies. This has prompted researchers to investigate the effect of modulation of the RAAS on progenitor cells. Furthermore, the relationship between hypertension and endothelial progenitor cell function is being studied. Pharmacotherapy by means of angiotensin II type 1 receptor antagonists or angiotensin-converting enzyme inhibitors has varying effects on progenitor cell levels and function. These controversial effects may be explained by involvement of multiple mediators, e.g. angiotensin II and angiotensin-(1–7), that have differential effects on mesenchymal stem cells, haematopoietic progenitor cells and endothelial progenitor cells. Importantly, angiotensin II can either stimulate endothelial progenitor cells by improvement of vascular endothelial growth factor signalling, or invoke excessive production of reactive oxygen species causing premature senescence of these cells. On the other hand, angiotensin-(1–7) stimulates haematopoietic cells and possibly also endothelial progenitor cells. Furthermore, aldosterone, bradykinin and Ac-SDKP (N-acetyl-Ser-Asp-Lys-Pro) may also affect progenitor cell populations. Alternatively, the variability in effects of angiotensin II type 1 receptor and angiotensin-converting enzyme inhibition on cardiovascular progenitor cells might reflect differences between the various models or diseases with respect to circulating and local tissue RAAS activation. In the present review we discuss what is currently known with respect to the role of the RAAS in the regulation of cardiovascular progenitor cells.

scholarly journals Ing4 Regulates Hematopoiesis through Suppression of NF-Kb

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 642-642
Author(s):  
Zanshe Thompson ◽  
Vera Binder ◽  
Michelle Ammerman ◽  
Ellen Durand ◽  
Leonard I. Zon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Target Gene ◽  
Target Genes ◽  
Zebrafish Embryos ◽  
Self Renewal ◽  
Hematopoietic Stem

Abstract Hematopoiesis is tightly regulated by a network of transcription factors and complexes that are required for the maintenance and development of HSCs. In a screen for epigenetic regulators of hematopoiesis in zebrafish, we identified a requirement of the tumor suppressor protein, Ing4, in hematopoietic stem and progenitor cell (HSPC) specification. Though the Ing4 mechanism of action remains poorly characterized, it has been shown to promote stem-like cell characteristics in malignant cells. This activity is, in part, due to the inhibitory role of Ing4 in the NF-kB signaling pathway. In the absence of Ing4, there is a significant increase in NF-kB target gene expression. As in the zebrafish, we have identified a requirement for Ing4 in murine hematopoiesis, where Ing4 deficiency impairs hematopoietic stem cell (HSC) function, but enhances multipotent progenitor cell (MPP) regenerative capacity. Given the role of Ing4 in both normal hematopoiesis and cancer, this gene likely has a critical role in regulation of stem cell self-renewal and maintenance. To define the role of Ing4 in zebrafish HSPCs, we designed an anti-sense morpholino oligo against Ing4 and injected into zebrafish embryos at the single cell stage. Embryos were screened using in situ hybridizations for c-myb and runx1 expression, which are highly expressed in the aorta, gonad, mesonephros (AGM) region in the developing zebrafish embryo. We found that Ing4-deficient zebrafish embryos lose >90% of runx1+/c-myb+ cells in the AGM, demonstrating a lack of HSPC specification. Analysis of ephrinB2 expression showed normal specification of the aorta in Ing4 morphant embryos, signifying that the step of HSPC specification is affected in the absence of Ing4. Overexpression of human Ing4 in zebrafish embryos resulted in increased HSPC marker staining suggesting that normal expression levels of Ing4 are required for HSC specification. As Ing4 is an epigenetic regulator that binds specific gene loci, we examined the chromatin occupancy of Ing4 in human peripheral blood CD34+ progenitor cells. Using ChIP-seq for Ing4 in CD34+ cells, we show that Ing4 binds to many regulators of blood development including MYB, LMO2, RUNX1, and IKAROS, and several NF-kB target genes. In other tissues, Ing4 negatively regulates NF-kB, so accordingly, loss of Ing4 results in an overabundance of NF-kB signaling. To address NF-kB target gene expression in Ing4-deficient zebrafish embryos, we performed qPCR analysis at 36hpf. These assays showed an increase in the expression of a subset of NF-kB target genes (IKBKE, IL-19, IL-1b, IL-20R). Simultaneous knockdown of both Ing4 and RelA, through combined morpholino injections against both factors, resulted in the rescue of HSC marker expression in the aorta. These results suggest that NF-kB inhibition could remediate the loss of Ing4. A mouse model for Ing4 deficiency was generated to further evaluate the role of Ing4 in differentiated immune cells. These mice are developmentally normal but are hypersensitive to stimulation with LPS. Interestingly, we found that Ing4-/- mice showed skewed hematopoiesis resulting in an increase in the number of short term-HSCs (ST-HSCs) (11.4% vs 31.7%) and a dramatic decrease in multipotent progenitor cells (MPPs) (47.9% vs 19.3%) along with concurrent modest increase in the population of long-term HSCs (LT-HSCs) (2.4% vs 5.5%). Additionally, there were alterations in stress hematopoiesis following hematopoietic stem cell transplant. Sorted LT-HSCs fail to engraft, suggesting an evolutionarily conserved requirement for Ing4 in HSCs. Surprisingly, competitive transplantation assay with Ing4-defecient MPPs versus wild-type showed dramatic increase in peripheral blood multilineage chimerism up to 9 months post-transplantation (19% vs. 59%). This lends to the hypothesis that Ing4 deficient MPPs gain self-renewal capabilities. Based on these exciting findings, we hypothesize that Ing4 normally functions as a critical suppressor for genes required for self-renewal and developmental potency in MPPs. Overall, our findings suggest that Ing4 plays a crucial role in the regulation of hematopoiesis and provides key tools for further identification and characterization of Ing4 pathways and functions. Disclosures No relevant conflicts of interest to declare.

scholarly journals Understanding the Regulatory Mechanisms of Endometrial Cells on Activities of Endometrial Mesenchymal Stem-Like Cells During Menstruation

2020 ◽  
Author(s):  
Shan Xu ◽  
Rachel W.S. Chan ◽  
Tianqi Li ◽  
Ernest H.Y. Ng ◽  
William S.B. Yeung
Keyword(s):  
Stem Cells ◽  
Progenitor Cells ◽  
Stromal Cells ◽  
Mrna Level ◽  
Phenotypic Expression ◽  
Luciferase Reporter ◽  
Menstrual Phase ◽  
Self Renewal ◽  
Endometrial Cells

Abstract Background: The identification of endometrial stem/progenitor cells in a high turnover rate tissue suggests that a well-orchestrated underlying network controls the behaviour of these stem cells. The thickness of the endometrium can grow from 0.5 – 1 mm to 5 – 7 mm within a week indicating the need of stem cells for self-renewal and differentiation during this period. The cyclical regeneration of the endometrium suggests specific signals can activate the stem cells during or shortly after menstruation. Methods: Endometrial mesenchymal stem-like cells (eMSCs) were cocultured with endometrial epithelial or stromal cells from different phases of the menstrual cycle, the clonogenicity and the phenotypic expression of eMSC markers (CD140b and CD146) were assessed. The functional role of WNT/β-catenin signalling on eMSC was determined by Western blot analysis, immunofluorecent staining, flow cytometry, quantitative real-time PCR and small interfering RNA. The cytokine levels in the conditioned medium of epithelial or stromal cells cocultured with eMSCs was evaluated by enzyme-linked immunosorbent assays. Results: Coculture of endometrial cells (epithelial or stromal) from the menstrual phase enhanced the clonogenicity and self-renewal activities of eMSCs. Such phenomenon was not observed in niche cells from the proliferative phase. Coculture with endometrial cells from the menstrual phase confirmed an increase in expression of active β-catenin in the eMSCs. Treatment with IWP-2, a WNT inhibitor suppressed the observed effects. Anti-R-spondin-1 antibody reduced the stimulatory action of endometrial niche cells on WNT/β-catenin activation in the T-cell factor/lymphoid enhancer-binding factor luciferase reporter assay. Moreover, the mRNA level and protein immunoreactivities of leucine-rich repeat-containing G-protein coupled receptor 5 were higher in eMSCs than unfractionated stromal cells. Conditioned media of endometrial niche cells cocultured with eMSCs contained increased levels of C-X-C motif ligand 1 (CXCL1), CXCL5 and interleukin 6. Treatment with these cytokines increased the clonogenic activity and phenotypic expression of eMSCs. Conclusions: Our findings indicate a role of WNT/β-catenin signalling in regulating activities of endometrial stem/progenitor cells during menstruation. Certain cytokines at menstruation can stimulate the proliferation and self-renewal activities of eMSCs. Understanding the mechanism in the regulation of eMSCs may contribute to treatments of endometrial proliferative disorders such as Asherman’s Syndrome.

scholarly journals Evaluation of Endothelial and Vascular-Derived Progenitor Cell Populations in the Proximal and Distal UCL of the Elbow: A Comparative Study

2018 ◽  
Vol 6 (6) ◽  
pp. 232596711877782 ◽  
Author(s):  
Salvatore J. Frangiamore ◽  
Elizabeth R. Morris ◽  
Alex C. Scibetta ◽  
Jorge Chahla ◽  
Gilbert Moatshe ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Smooth Muscle Actin ◽  
Rank Test ◽  
Cell Populations ◽  
Fluorescent Staining ◽  
Collateral Ligament ◽  
Signed Rank ◽  
Wilcoxon Signed Rank Test ◽  
Signed Rank Test

Background: Vascular-derived progenitor and endothelial cell populations (CD31, CD34, CD146) are capable of multipotent differentiation at the site of injured ligamentous tissue to aid in the intrinsic healing response. Proximal ulnar collateral ligament (UCL) tears have been reported to have better healing capability when compared with distal UCL tears. Purpose: To compare the vascular composition of the proximal and distal insertions of the anterior bundle of the UCL of the elbow via known markers of endothelial and vascular-derived progenitor cells (CD31, CD34, CD146). Study Design: Descriptive laboratory study. Methods: UCLs were harvested from 10 nonpaired fresh-frozen human cadaveric elbows and transected into proximal and distal portions. Endothelial and vascular-derived progenitor cell densities were assessed with 4 staining groups: CD31 (immunohistochemistry) and CD31/α-smooth muscle actin (α-SMA), CD34/α-SMA, and CD146/α-SMA (immunofluorescence). CD31 immunohistochemistry identified endothelial progenitor cells in the UCL. Later staining of the same slides with α-SMA demonstrated the relationship of progenitor cells to the surrounding vasculature. Fluorescent staining was quantified by calculating the proportion of positively stained nuclei versus the total number of nuclei in the proximal and distal UCL. Results: CD31+ cells were present in the proximal and distal sections of all 10 UCLs. Fluorescent staining revealed no significant differences in the ratio of CD31 to total nuclei between the distal (median, 36% [range, 23%-53%]) and proximal UCL (39% [22%-56%]) ( P = .432, Wilcoxon signed-rank test). Similarly, no differences were seen between CD34 distal (39% [24%-64%]) and proximal regions (46% [28%-63%]) ( P = .846, Wilcoxon signed-rank test) or CD146 distal (40% [12%-65%]) and proximal regions (40% [22%-51%]) ( P ≥ .999, Wilcoxon signed-rank test). Conclusion: Analysis of UCL tissues demonstrated equal distributions of vascular endothelial and vascular-derived progenitor cell markers throughout the proximal and distal UCL. Unlike that of the medial collateral ligament of the knee, the microvascular composition of the proximal and distal UCL insertions was not different, suggesting a well-vascularized ligament throughout its course. Clinical Relevance: These findings investigate one of the possible contributors to UCL healing after injury, which may provide insight into operative and nonoperative management of UCL injuries in the future. This study also indicates that reasons other than differences in progenitor cell density alone may explain the clinical healing differences seen between proximal and distal UCL tears. A better understanding of the microvascular environment and associated blood supply is warranted to understand the healing capability of the UCL.

scholarly journals Eosinophil Lineage-Committed Progenitors as a Therapeutic Target for Asthma

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 412
Author(s):  
Brittany M. Salter ◽  
Xiaotian Ju ◽  
Roma Sehmi
Keyword(s):  
Progenitor Cells ◽  
Clinical Outcomes ◽  
Progenitor Cell ◽  
Treatment Strategies ◽  
Eosinophilic Asthma ◽  
Airway Eosinophilia ◽  
Tissue Eosinophilia ◽  
Bronchial Tissue ◽  
Hemopoietic Progenitor

Eosinophilic asthma is the most prevalent phenotype of asthma. Although most asthmatics are adequately controlled by corticosteroid therapy, a subset (5–10%) remain uncontrolled with significant therapy-related side effects. This indicates the need for a consideration of alternative treatment strategies that target airway eosinophilia with corticosteroid-sparing benefits. A growing body of evidence shows that a balance between systemic differentiation and local tissue eosinophilopoietic processes driven by traffic and lung homing of bone marrow-derived hemopoietic progenitor cells (HPCs) are important components for the development of airway eosinophilia in asthma. Interleukin (IL)-5 is considered a critical and selective driver of terminal differentiation of eosinophils. Studies targeting IL-5 or IL-5R show that although mature and immature eosinophils are decreased within the airways, there is incomplete ablation, particularly within the bronchial tissue. Eotaxin is a chemoattractant for mature eosinophils and eosinophil-lineage committed progenitor cells (EoP), yet anti-CCR3 studies did not yield meaningful clinical outcomes. Recent studies highlight the role of epithelial cell-derived alarmin cytokines, IL-33 and TSLP, (Thymic stromal lymphopoietin) in progenitor cell traffic and local differentiative processes. This review provides an overview of the role of EoP in asthma and discusses findings from clinical trials with various therapeutic targets. We will show that targeting single mediators downstream of the inflammatory cascade may not fully attenuate tissue eosinophilia due to the multiplicity of factors that can promote tissue eosinophilia. Blocking lung homing and local eosinophilopoiesis through mediators upstream of this cascade may yield greater improvement in clinical outcomes.

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