Bone Marrow Stem Cell Chemotactic Activity Is Induced by Elevated CXCl12 in Endometriosis

Abstract

Endometriosis is an inflammatory gynecological disorder caused by the growth of endometrial tissue outside the uterus. Endometriosis produces chemokines, including CXCL12, that attract bone marrow cells to the lesions. In this study, we describe the expression, localization, and chemotactic activity of CXCL12 in endometriotic lesions. Biopsies were collected both from women with endometriosis undergoing laparoscopy and control endometrium from women without endometriosis. Expression of CXCl12 and CXCR4 messenger RNA was increased approximately 4-and 6-fold, respectively, in endometriosis compared to eutopic endometrium. Immunohistochemistry of lesions revealed that CXCR4 was expressed in the stroma and epithelium in both endometriosis and control eutopic endometrium. The level of CXCR4 protein expression was significantly higher in all cellular compartments of the endometriotic lesions compared to control endometrium. CXCL12 protein expression was also higher in endometriotic lesions and was greatest in the epithelial compartment. CXCL12 was increased more in the condition media of cultured endometriosis than in controls as measured by enzyme-linked immunosorbent assay. Transwell chamber migration was used to demonstrate 2-fold increased chemoattraction of mouse bone marrow stem cells toward CXCL12 in the endometrioticconditioned medium compared with eutopic endometrium. Our results indicate that a preferential recruitment of stem cells to endometriosis can explain how endometriosis outcompetes eutopic endometrium in recruiting the limited supply of circulating stem cells. The CXCL12/CXCR4 signaling axis is a potential target for the treatment of endometriosis and its associated disorders.

Pathogenesis of endometriosis: the genetic/epigenetic theory

“…The mesothelial cell metaplasia theory, proposed in 1942 (31), has been expanded to metaplasia of peritoneal stem cells (215,(221)(222)(223)(224)(225)(226)(227)(228)(229)(230)(231), endometrial stem cells (232,233), and more recently bone marrow cells (221,225,(234)(235)(236)(237)(238), pale cells (239,240) and embryonic remnants (241)(242)(243). These concepts find support in the frequent mesothelialmesenchymal transitions with a role of platelets (244) and in the role of bone marrow cells in peritoneal repair (245).…”

Pathogenesis of deep endometriosis

“…Mesothelial-to-mesenchymal transition in the peritoneal cavity is well known (124,125) with a specific role of platelets (48). Some of these mesenchymal/ mesothelial cells of the peritoneal cavity (48), of the mesothelial repair after surgery (126) and in endometrium and endometriosis (127)(128)(129)(130)(131) are directly derived from bone marrow. Endometriosis could develop from stem cells in the endometrium (132,133) or in the peritoneal cavity (29,(134)(135)(136)(137)(138)(139)(140)(141)(142)(143)(144), possibly induced by genetic changes (60).…”

CXCR4 or CXCR7 antagonists treat endometriosis by reducing bone marrow cell trafficking

“…CXCR4, a G protein‐coupled receptor (GPCR), is a receptor for CXCL12 expressed by bone marrow‐derived mesenchymal stem cells. CXCL12‐CXCR4 signalling is increased in women with endometriosis and has been established as a crucial signal for BMDCs migration to endometriosis …”

“…CXCL12-CXCR4 signalling is increased in women with endometriosis 20,21 and has been established as a crucial signal for BMDCs migration to endometriosis. 22 CXCR7, also a GPCR, was recently identified as another receptor for CXCL12. 23,24 CXCR7 is phylogenetically closely related to other chemokine receptors and binds CXCL12 with a higher affinity than CXCR4, but it fails to couple to G proteins to induce typical chemokine receptor-mediated cellular responses.…”