Cigarette smoke inhibits recruitment of bone-marrow-derived stem cells to the uterus

Abstract

Cigarette smoking leads to female infertility and a decreased incidence of endometriosis. Bone marrow derived stem cells are recruited to uterine endometrium and endometriosis. The effect of cigarette smoking on stem cell recruitment to any organ is uncharacterized. We hypothesized that bone marrow-derived mesenchymal stem cell recruitment to the uterus and differentiation would be diminished by cigarette smoke. We used human mesenchymal stem cells (hMSC) in vitro and a mouse model of cigarette smoke exposure. After myeloablation female C57BL/6J received bone marrow cells from males. Mice were exposed to room air or smoke from unfiltered cigarettes. Immunofluorescence and Y-FISH was performed on uterine sections. In vitro hMSCs were treated with 8-Br-cAMP to induce endometrial cell differentiation with or without cigarette smoke extract (CSE) and decidualization assessed morphologically and by prolactin expression. After 4 weeks the total number of Y-chromosome cells in the uterus was reduced by 68% in the smoke exposed mice. Both leukocytes and bone marrow derived endometrial cells were reduced by 60% and 73%, respectively. Differentiation of bone marrow derived cell to endometrial epithelial cells was reduced by 84%. hMSC treated with CSE failed to show cytological characteristics of decidualization. mRNA levels of the decidualization marker prolactin were decreased by 90% in CSE treated cells. Smoking inhibits both recruitment of bone marrow derived stem cells to uterus and stem cell differentiation. Inhibition of stem cells recruitment may be a general mechanism by which smoking leads to long term organ damage through inability to repair or regenerate multiple tissues.

Experimental Evidence for Bone Marrow as a Source of Nonhematopoietic Endometrial Stromal and Epithelial Compartment Cells in a Murine Model1

“…These findings are provocative, supporting the ability of BMDCs to generate endometrial cells de novo. The finding that human bone marrow-derived mesenchymal stem cells can differentiate in vitro into endometrial decidual cells when exposed to 8-bromo-cyclic adenosine monophosphate (a potent decidualizing agent of human endometrial stromal cells) further supports the bone marrow as a source of endometrial cells [14,18].…”

“…Distinct from the few prior murine in vivo studies which support the concept of the bone marrow as a source of endometrial cells [9,[12][13][14][15], the present studies are the first to evaluate engraftment of the endometrium with bone marrow-derived cells at multiple time points post bone marrow transplant. We followed recipient animals for as long as 12 months post transplant to assess for long term engraftment of the uterus with bone marrow-derived cells.…”

“…The laboratory of Taylor and colleagues [12] identified Y chromosome-positive endometrial epithelial and stromal cells in female recipients of BMT from male donors six months post-transplant. These investigators subsequently demonstrated in a male-to-female murine BMT model that migration of BMDCs to the endometrium is promoted by ischemic uterine injury [15], and inhibited by exposure to cigarette smoke [14]. A male-to-female murine transplant model was also used by the laboratory of Mints and colleagues, who identified endothelial cells of donor origin in recipient endometria 40 days post-transplant [9], but did not evaluate whether other endometrial cell types were donor-derived.…”

“…Although recent in vivo data from human [8][9][10][11] and murine [9,[12][13][14][15] model systems support the concept that the bone marrow is an important contributor of stem cells to the endometrium, these prior studies have several limitations. Human studies which have demonstrated bone marrow-derived endometrial cells in bone marrow transplant recipients are severely limited in the number of subjects studied.…”

Stem Cell as the Novel Pathogenesis of Endometriosis

“…The treatment target can focus on the inhibition of stem cell flux and initiation and progression of endometriosis. Recent report (Zhou et al, 2011) cigarette smoke inhibits recruitment of bone marrow derived stem cells to the uterus. This finding is compatible with the epidemiological data of low incidence of endometriosis cases in smokers.…”