{"paper_id":"ca9939fd-26bc-4d19-9271-1001fae0eb24","body_text":"Developing Therapies that Prevent Progenitor \nCell Migration for Preventing the Development \nand Further Growth of Endometriotic Lesions-\nFuture Prospects-A Short Communication\nKulvinder Kochar Kaur*1, Gautam Allahbadia1 and Mandeep Singh2\n1Centre for Human Reproduction, India\n2Department of Neurologist, India\nShort communication\nEndometriosis represents a frequent as well as benign gynecological disease that is \ndefined as the presence of endometrial tissue (glands as well as stroma) in sites external \nto the normal endometrium as well as rest of the parts of uterus [1]. About 10% of women \nof childbearing age have endometriosis with the rate escalating in recent years. There \nis an immediate need for getting efficacious therapies. Earlier we had reviewed on the \netiopathogenesis ,management of Endometriosis as well as Adenomyosis in infertile patients \n,effect on oocytes along with Endometriosis in adolescents and effectively managing both pain \nas well as infertility along with preventing risk of malignancy in endometriosis but still no \npermanent solution is coming hence the endeavor to keep looking for newer avenues [2-8].\nIt is known that Endometriosis is an estrogen associated disease ,along with \nneovascularization having a crucial part in its establishment ,propagation as well as recurrence \n.It has been shown that via mobilization as well as recruitment of endothelial progenitor \ncells (EPC’s) estrogen has significant role in neovascularization [9,10]. Further estrogen can \ninduce the endometriotic lesions escalating [11,12]; (Figure 1 & 2), with some recent studies \nillustrating that therapy with estrogen facilitates vasculogenesis in endometriotic lesions \nvia enhancing amounts of EPC’s [13]. Chemokine receptor 4(CXCR4) is a key manipulator \nregarding homing of EPC’s [14], while Li et al. [13], demonstrated that estrogen escalates the \nrecruitment of EPC’s to the areas of damage through the stromal cell derived factor(SDF1)-\nCXCR4 pathways in myocardial infarction(MI) [11]. Certain studies have illustrated that \nestrogen increases the SDF1/CXCR12 synthesis in human Endometrial stromal cells (HESCs)\nin a time as well as dose-based fashion [11]. Nevertheless, the part as well as mode of SDF1/\nCXCR12 in endometriosis is not understood.\nCK2 represents a serine/threonine kinase made up of 2 catalytic (α or α’)subunits as well \nas 2 regulatory (β) subunits, that assemble in the form of a tetramer.CK2 can phosphorylate \nsubstrates to control a lot of biological events [15]. Earlier Feng et al. [16], showed that CK2 \ncontrols angiogenesis of endometriotic lesions along with a protein kinase CK2 inhibitor \ninhibits the development of new blood vessel’s as well as growth of endometriotic lesions. \nStill it was not clear what is the insight in CK2 controls of EPC’s at the time of vasculogenesis \nin endometriotic lesions [17]. Endometriosis has been known to be crucially based on actively \ngoing angiogenesis and thus new blood vessels represent a mark of the lesions. Trying to get \nmethods of blocking this angiogenesis as well as vasculogenesis might help in innovative ways \nof tackling endometriosis. Bone marrow (BM)-derived endothelial cells aid in vasculogenesis, \nthat includes the ones for endometriosis as well as uterus at the time of pregnancy [18]. In \nview of their part in endometriosis lesions as well as recruitment during active disease, these \nendothelial progenitor cells are good targets for therapeutic intervention.\nCrimson Publishers\nWings to the Research Short Communication\n*Corresponding author: Kulvinder Kochar \nKaur, Centre for Human Reproduction, \nIndia\nSubmission: \n  June 24, 2020\nPublished: \n  July 10, 2020\nVolume 3 - Issue 5\nHow to cite this article:  Kulvinder \nKochar Kaur, Gautam Allahbadia, \nMandeep Singh. Developing Therapies \nthat Prevent Progenitor Cell Migration \nfor Preventing the Development and \nFurther Growth of Endometriotic Lesions-\nFuture Prospects-A Short Communication. \nPerception in Reproductive Medicine.3(5). \nPRM.000575.2020.\nDOI: 10.31031/PRM.2020.03.000575\nCopyright@ Kulvinder Kochar Kaur, This \narticle is distributed under the terms of \nthe Creative Commons Attribution 4.0 \nInternational License , which permits \nunrestricted use and redistribution \nprovided that the original author and \nsource are credited.\nISSN: 2640-9666\n261Perception in Reproductive Medicine\n\n262\nPerceptions Reprod Med\n      Copyright © Kulvinder Kochar Kaur\nPRM.MS.ID.000575. 3(5).2020\nFigure 1: Courtesy ref no-12-Localization of human endometrial mesenchymal stem cells. (A-C) Immunofluorescence \nimages of human endometrium showing perivascular identity of human eMSCs. \na. Co-localization (white arrows) of CD146 and platelet-derived growth factor receptor beta (PDGF-Rβ) in pericytes \nof venules and possibly capillaries in the functionalism stroma. The x/z and y/z planes are shown on the far right and \nunderneath the merged images demonstrating co-localization of the two surface markers. \nb. Perivascular SUSD2 expression (white arrows). \nc. ATP-binding cassette, subfamily G member 2 (ABCG2) and αSMA co-staining showing perivascular and \nendothelial identity of SP cells. The white dotted lines indicate the junction between the endometrium (en) and \nmyometrium (my) and yellow dotted line indicates the luminal surface (lu) of the uterine epithelium. (D) Schematic \nshowing location of stem/progenitor cells identified in the human endometrium. \nEpithelial progenitor cells are postulated to be a subpopulation of cells located in the base of the glands in the basalis, \nidentified by SSEA-1. Sushi domain containing-2+ (SUSD2+) eMSCs are perivascular cells. eMSC co-expressing CD146 \nand PDGFRβ/CD140b are most likely pericytes, as they are located adjacent to endothelial cells in vessels (v) in both \nthe basalis and the functionalism. SP cells are a heterogeneous population comprising CD31+ endothelial cells and \nCD140b+CD146+ pericytes. Scale bar in (A)=50µm. (A) Reprinted with permissions from Schwab and Gargett [12]. (C) \nReprinted with permissions from Masuda et al. (2010). (D) Adapted from Gurung et al. (2015).\nFigure 1: Courtesy ref no- 12-Schematic describing the hypothesis that endometrial stem/progenitor cells shed in \nneonatal uterine bleeding may play a role in early onset endometriosis. Neonatal uterine bleeding occurs in 5% \nof neonates. It is hypothesized that retrograde neonatal bleeding occurs because thick mucus obstructs the long \nneonatal cervix. Fragments of shed endometrial tissue are postulated to contain an endometrial epithelial progenitor \ncell (pink) and a perivascular MSC (pink) together with niche cells. These rapidly adhere to the neonatal mesothelium, \ninvade and/or become contiguous with the mesothelial lining where they remain quiescent for ∼10 years. Rising \nestrogen (E2) levels associated with thelarche and menarche reactivate the stem/progenitor cells to initiate growth of \nendometriosis lesions on the surface of or below the peritoneal mesothelium, resulting in early onset endometriosis. \nReprinted with permissions from Gargett et al. (2014).\n\n263\nPerceptions Reprod Med       Copyright © Kulvinder Kochar Kaur\nPRM.MS.ID.000575. 3(5).2020\nBoth in endometrial as well as decidual physiology as well as \npathology like endometriosis bone marrow (BM)-derived cells \nhave a proven part. Stem cells via BM engraft normal endomerium \nand help in this endometrium repair following injury. BM-derived \nstem cell become decidual cells along with support pregnancy \nplaying a necessary role [19]. Thus these BM-derived stem cells get \ntransported within the circulation along with getting recruited to \nalong with engrafted in endomerium is a part of normal physiology, \nCXCL12 represent a strong chemoattractant which results in \nmigration as well as engraftment of BM cells in normal endomerium \nas well as Endometriosis [19]. Taylor’s group earlier demonstrated \nthat endometriosis synthesis large amounts of CXCL12 (also \ncalled stromal derived factor 1[SDF1] [20]. Estrogen activates the \nsynthesis as well as liberation of CXCL12. BM cells which get moved \nto e endometriosis by the attraction of CXCL12 are a subpopulation \nof endothelial progenitor cells. These endothelial progenitor cells \nare circulating cells which stick to the endomerium at the areas \nof hypoxia or ischemia and aid in new vessel development. These \nstem cells getting incorporated is key for blood vessels growth as \nwell as progression of endometriosis.\nThe control of CXCL12 expression by the protein kinase CK2 has \nbeen found by Zhao et al. [21]. The same group earlier demonstrated \nthat CK2 controls angiogenesis within these Endometriosis lesions. \nBlockade of this enzyme avoids development of new blood vessels \nas well as growth of Endometriosis. This ubiquitous as well as \nconstitutively active serine threonine kinase has been shown to be \ncontrolled via estrogen, whose activity thus escalates CXCL12. This \nCXCL12 attracts endothelial progenitor cells, by a mode by which \nthese cells get homed to endometriosis lesions. By blocking this \npath at any junction blocks endothelial cell migration, depletion \nof estradiol(E2). On blocking CK2 action with its potent as well \nas selective inhibitor CX4945, or with usage of CXCL12 receptor \nantagonist AMD3100 all inhibit this signaling path. In the same \nway Taylor showed in animal models of endometriosis recently \nregarding AMD3100 inhibits stem cell migration to endometriosis \nand thus results in regression of these lesions [22].\nConclusion\nWill therapy with agents that block CK2 have the capacity as \ntreatment of endometriosis? CK2 represents a pleiotropic protein \nkinase, that controls lot of growth as well as survival paths in \nnormal cells as well as disease. Though CK2 inhibitors CX4945 \nhas been formed for treatment of cancers ,with its nonspecific \neffect on practically all tissues, risk of off target actions is high, and \nthus makes it unlikely to be used for endometriosis therapy .But \nthis gives a lot of lessons regarding blockade of signaling path that \nends in endothelial cell engraftment of endometriosis. Inhibition of \nCXCL12. Action by using AMD3100 holds promise and has realistic \nnew way of Endometriosis therapy as shown in murine models of \nEndometriosis [23]. More significant, we get insight that estrogen \ndepriving controls CK2, CXCL12 as well as endothelial cell migration. \nProgestin therapy does not add this benefit. The therapies used \ncurrently for decreasing Estrogen are Gn RH agonists, aromatase \ninhibitors. Though this suddenly is not possibly help in future \nforming agents which block CK2 to be included as agents for \nEndometriosis therapy regimens we have got insight that standard \ntherapies will inhibit endothelial cell engraftment as well as lesion \nexpansion. Considering non hormonal therapy CXC R4 antagonist \nhave>specificity as well as less toxic as compared to CK2 inhibitors, \nbut action on pregnancy is not well known. Decrease of estrogen \nwill also block cell engraftment. Thus, E2 deprivation remains gold \nstandard for Endometriosis therapy till now. \nReferences\n1. Giudice LC (2010) Endometriosis. N Engl J Med 362: 2389-2398.\n2. Kulvinder Kochar K, Allahbadia GN, Singh M (2017) Current controversies \nand future challenges in endometriosis therapy. EC Gynaecology 1: 9-13.\n3. Kulvinder Kochar K, Allahbadia GN, Singh M (2016) An update on \npathophysiology and medical management of endometriosis. Advances \nin Repr Sci 4(2): 53-73. \n4. Kulvinder Kochar K, Allahbadia GN, Singh M (2017) Meeting the \nchallenges of endometriosis associated pain-newer options for future \nand research directions. BAOJ Bioinfo 1: 9. \n5. Kulvinder Kochar K, Allahbadia GN, Singh M (2019) An update on \ndiagnosis and management of adolescent endometriosis -A short \ncommunication. Acta Scientific Paediatrics 2(5): 48-50. \n6. Kulvinder Kochar K, Allahbadia GN, Singh M (2019) Dissecting the \nreduced ovarian reserve seen with ovarian enometriomas with that \ncaused by surgical excision of ovarian enometriomas-what comes first. \nSurg Med Open Acc J 2(2). \n7. 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(2010) \nReconstitution of PTEN activity by CK inhibitors and interference with \nthe PIK3/Akt cascade counteract the antiapoptotic effect of human \n\n264\nPerceptions Reprod Med       Copyright © Kulvinder Kochar Kaur\nPRM.MS.ID.000575. 3(5).2020\nstromal cell in chronic lymphocytic leukaemia. Blood 116: 2513-2521.\n16. Feng D, Welker S, Korbel C, Auth RJ, Menger MD, et al. (2012) Protein \nkinase CK2 is a regulator of angiogenesis of Endometriotic lesions. \nAngiogenesis 15(2): 243-252.\n17. Montenarh M (2014) Protein kinase CK2 and angiogenesis. Adv Clin Exp \nMed 23(2): 153-158.\n18. Tal R, Dong D, Shaikh S, Manallapalli R, Taylor HS (2019) Bone marrow-\nderived endothelial progenitor cells contribute to vasculogenesis of \npregnant mouse uterus. Biol Reprod 100(5): 1228-1237.\n19. Tal R, Shaikh S, Pallavi D, Tal A, Giraldez LF, et al. (2019) Adult bone \nmarrow progenitors become decidual cells and contribute to embryo \nimplantation and pregnancy. PLoS Biol 17(9): e3000421.\n20. Li F, Alderman MH, Tal A, Manallapalli R, Coolidge A, et al. (2018) \nHaematogenous dissemination of mesenchymal stem cells from \nEndometriosis. Stem Cells 36(6): 881-890.\n21. Zhao RM, Feng D, Zhuanf G, Liu Y, Chi S, et al. (2020) Protein kinase \nCK2 participates in estrogen mediated endothelial cell homing to \nEndometriosis lesions through stromal cells in an SDF1- CXC R4 \ndependent manner. Fertil Steril 113(5): 1067-1079.\n22. Plochino N, Manallapalli R, Shaikh S, Habata S, Tal A, et al. (2020) CXC \nR4 or CXC R7 antagonists treat endometriosis by reducing bone marrow \ncell trafficking. J Cell Mol Med 24: 2464-2474.\n23. Taylor HS (2020) Bone marrow in the pathophysiology of Endometriosis. \nFertil Steril 113: 942-942.\nFor possible submissions Click below: \nSubmit Article","source_license":"CC0","license_restricted":false}