Liver Sinusoidal Endothelial Cells Promote B Lymphopoiesis From Primitive Hematopoietic Cells

Abstract

Although the bone marrow (BM) microenvironment is the main inducer niche of early B lymphopoiesis during the adult life, other extramedullar microenvironments, such as the liver, may also have potential for supporting B-cell development. Previously, we reported that murine liver sinusoidal endothelial cells (LSECs) support in vitro and in vivo hematopoietic stem cell (HSC) proliferation and myeloid differentiation. In the present study, we investigated the capacity of LSEC to promote B lymphopoiesis from BM progenitor lineage-negative (Lin(-)) cells. Murine BM Lin(-) cells were co-cultured with LSEC, in the absence of exogenous cytokines. B cells were characterized by flow cytometry and cytokine expression by RT-PCR. We show that BM Lin(-) cells differentiated to early B-lymphoid progenitors (B220(+)) and subsequently to mature (CD19(+)) B cells. Functional studies showed the presence of a high number of non-adherent cells (NACs), collected from lipopolysaccharide (LPS)-treated Lin(-)/LSEC co-cultures, expressing IgM on their surface (sIgM). Colony formation from NAC was observed in the presence of IL-7 (CFU-IL-7). LSEC constitutively express IL-7, Flt-3L, and SCF at the mRNA level, and VCAM-1 on their surface, which may explain the capacity of these cells to promote B lymphopoiesis. These data demonstrate that LSEC promote all stages of B lymphopoiesis. To our knowledge, this is the first report that LSEC constitute an in vitro microenvironment for B lymphopoiesis. Further studies will establish whether LSEC can serve in vivo as a B-lymphopoietic niche under physiological or pathological condition, or when HSC are mobilized.

Hematopoietic Microenvironment in the Fetal Liver: Roles of Different Cell Populations

“…Due to the expression of cell adhesion molecules such as E-selectin and VCAM-1 [50,51] and chemoattractants such as stromal cell-derived factor-1 [52], the sinusoidal endothelium in the fetal liver can control the homing of hematopoietic cells, their retention in the niche, and release into the circulation. In the fetal liver, hematopoietic stem cells interact with the sinusoidal endothelium via activated protein C. This interaction facilitates self-renewal of the stem cells and prevents their apoptosis [53].…”

“…Moreover, endothelial cell lines or medium conditioned by them maintain in vitro differentiation of erythroid and granulocytemacrophage lineage cells [54,55], which is evidence for the ability of endotheliocytes to regulate hematopoiesis via contact interactions with hematopoietic cells and secretion of cytokines. Fetal liver endothelial cells can also promote Blymphopoiesis from primitive hematopoietic cells [51].…”

Skeletogenesis and the Hematopoietic Niche

“…chemokine and adhesion molecule expression, not only allow them to be conduits for hematopoietic cells to and from the circulation, but also to serve as an area for HSPC differentiation (Rafii et al 1994;Rafii et al 1995;Schweitzer et al 1996;Naiyer et al 1999;Abkowitz et al 2003;Avecilla et al 2004). In agreement, endothelial cells from several sources are able to support HSPC maintenance and differentiation toward lymphoid and myeloid lineages in culture (Rafii et al 1995;Ohneda et al 1998;Li et al 2004;Wittig et al 2009;Butler et al 2010). Visualizing the vascular niche in vivo with a pure sub-set of HSCs also provided support for the vascular niche theory.…”

“…cytokines, chemokines, hormones, and growth factors. Many soluble factors have been implicated in hematopoiesis, such as CXCL-12, SCF, Fmsrelated tyrosine kinase 3 ligand (Flt-3L), thrombopoietin (TPO), FGF, G-CSF, GM-CSF, LIF, Wnt, BMP-4, IL-3, 6, 7, 8, 11, 12, 14, 15 (Guba et al 1992;Heinrich et al 1993;Verfaillie 1993;Funk et al 1995;Rafii et al 1997;Taichman et al 1997;Peled et al 1999;Majumdar et al 2000;Ponomaryov et al 2000;Petit et al 2002;Avecilla et al 2004;Kortesidis et al 2005;Dar et al 2006;Jung et al 2006;Spiegel et al 2007;Wittig et al 2009), or in maintenance and quiescence of HSCs, e.g. Ang-1 and TGF (Eaves et al 1991;Fortunel et al 2000;Arai, F. et al 2004) (cytokine functions reviewed in (Zhang, C.C.…”

Human Olfactory Mucosa Multipotent Mesenchymal Stromal Cells Promote Survival, Proliferation, and Differentiation of Human Hematopoietic Cells

“…Our results showing that OM-MSCs promote lymphopoiesis from BMCs, in the absence of exogenous cytokines, may be explained by the capacity of these cells to constitutively express the lymphopoietic cytokine IL-7. Recent reports have also shown a restricted generation of B-lineage cells without using exogenous cytokines [59]. Other MSCs lines reported to promote hematopoiesis, in vitro, do not have the capacity to support lymphopoiesis in vitro [51].…”