title: Toll-like receptors 2 and 4 mediate the capacity of mesenchymal stromal cells to support the proliferation and differentiation of CD34⁺ cells.
abstract: Bone marrow derived-mesenchymal stromal cells (BM-MSCs) are multipotent, nonhematopoietic progenitors in a hematopoietic microenvironment and indispensable for regulating hematopoiesis. Several studies have reported that toll-like receptors (TLRs) are expressed in mesenchymal stromal cells (MSCs) to modulate their biological functions. In this study, we investigated the possible role(s) of TLRs in mediating the hematopoiesis-supporting role of human BM-MSCs. Human BM-MSCs were analyzed for mRNA expression of TLR1-10 by reverse transcription-polymerase chain reaction. TLR1-6, but not TLR7-10 were expressed by BM-MSCs. The protein expression of TLR2 and TLR4 was also confirmed by flow cytometry. We further explored the role of TLR2 and TLR4 in mediating the capacity of BM-MSCs to support the proliferation and differentiation of CD34(+) hematopoietic stem/progenitor cells obtained from cord blood. BM-MSCs increased proliferation of CD34(+) cells and promoted the differentiation towards the myeloid lineage 7 or 14days after co-culture, as well as colony formation by those cells and the production of interleukin 1 (IL-1), IL-8, IL-11, stem cell factor (SCF), granulocyte colony-stimulating factor (CSF), macrophage CSF and granulocyte-macrophage CSF, if MSCs had been stimulated with TLR2 agonist (PAM(3)CSK(4)) or TLR4 agonist (LPS). Interestingly, although these effects were elevated in a different degree, a synergistic effect was not observed in BM-MSCs co-stimulated with PAM(3)CSK(4) and LPS. Together, our findings suggest that TLR2 and TLR4 signaling may indirectly regulate hematopoiesis by modulating BM-MSCs' functions. The increased hematopoietic proliferation and differentiation could be mediated, at least in part, by augmented hematopoiesis-related cytokine production of BM-MSCs.
authors.affiliation: Department of Hematology of Anhui Provincial Hospital, Anhui Medical University, Hefei, Anhui, China. wangxingbing91@hotmail.com
authors.forename: Xingbing
authors.initials: X
authors.lastname: Wang
authors.forename: Qiansong
authors.initials: Q
authors.lastname: Cheng
authors.forename: Lailing
authors.initials: L
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Xia
authors.forename: Xiucai
authors.initials: X
authors.lastname: Xu
authors.forename: Zimin
authors.initials: Z
authors.lastname: Sun
mesh_terms: D018952:Antigens, CD34 / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000378:metabolism / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006410:Hematopoiesis / Q000235:genetics; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism; D017370:Interleukin-11 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D018952:Antigens, CD34; D007375:Interleukin-1; D017370:Interleukin-11; D016209:Interleukin-8; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor