CXCL12+ stromal cells as bone marrow niche for CD34+ hematopoietic cells and their association with disease progression in myelodysplastic syndromes

Abstract

The bone marrow microenvironment, known as 'hematopoietic stem cell niche,' is essential for the survival and maintenance of hematopoietic stem cells. Myelodysplastic syndromes (MDS) are a group of clonal hematopoietic stem cell diseases, which eventually result in leukemic transformation (acute myelogenous leukemia with myelodysplasia-related changes, AML-MRC). However, the precise components and functions of the MDS niche remain unclear. Recently, CXCL12-abundant reticular cells were shown to act as a hematopoietic stem cell niche in the murine bone marrow. Using immunohistochemistry, we show here that CXCL12 þ cells were located in the cellular marrow or perivascular area, and were in contact with CD34 þ hematopoietic cells in control and MDS/AML-MRC bone marrow. MDS bone marrow exhibited higher CXCL12 þ cell density than control or AML, not otherwise specified (AML-NOS) bone marrow. Moreover, AML-MRC bone marrow also exhibited higher CXCL12 þ cell density than control bone marrow. CXCL12 þ cell density correlated positively with bone marrow blast ratio in MDS cases. CXCL12 mRNA level was also higher in MDS bone marrow than in control or AML-NOS bone marrow. In vitro coculture analysis revealed that overexpression of CXCL12 in stromal cells upregulated BCL-2 expression of leukemia cell lines. Triple immunostaining revealed that the CD34 þ hematopoietic cells of MDS bone marrow in contact with CXCL12 þ cells were BCL-2-positive and TUNEL-negative. In the bone marrow of MDS cases, CXCL12-high group showed significantly higher Bcl-2 þ /CD34 þ cell ratio and lower apoptotic cell ratio than CXCL12-low group. Moreover, CXCL12-high refractory cytopenia with multilineage dysplasia (RCMD) cases had a greater tendency to progress to refractory anemia with excess blasts (RAEBs) or AML-MRC than CXCL12-low RCMD cases. These results suggest that CXCL12 þ cells constitute the niche for CD34 þ hematopoietic cells, and may be associated with the survival/antiapoptosis of CD34 þ hematopoietic cells and disease progression in MDS. Thus, CXCL12 þ cells may represent a novel MDS therapeutic target.

Pharmaceutical efficacy of human epiphyseal chondrocytes with differential replication numbers for cellular therapy products

“…Chondrocytes at a primary culture from articular cartilage show mature and well-formed cartilage with extracellular matrix of type-II collagen, however those with chondrocytes with a longer cultivation do not generate cartilage with type-II collagen but form fibrous tissue [16] and almost same results have been presented in chondrocytes from the costal cartilage [17]. Chondrocytes can be not only isolated from cartilage, but also differentiated from somatic stem cells including mesenchymal stem cells and marrow stromal cells [2, 20-23]. Chondrocytes have recently been generated from pluripotent stem cells like other cell types [2, 24-27].…”

Concise Review: The Malignant Hematopoietic Stem Cell Niche

“…Alterations in the bone marrow microenvironment are also seen in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In MDS, in contrast to ALL, CXCL12 expression is increased . This is due, at least in part, to the expansion of CXCL12‐positive CD271 + perivascular stromal cells .…”

“…In MDS, in contrast to ALL, CXCL12 expression is increased . This is due, at least in part, to the expansion of CXCL12‐positive CD271 + perivascular stromal cells . A recent study reported that in 38% of cases of MDS or AML, increased β‐catenin signaling and β‐catenin nuclear accumulation in osteoblasts are present .…”

Ubiquitous overexpression of CXCL12 confers radiation protection and enhances mobilization of hematopoietic stem and progenitor cells

“…Cytokines and chemokines play essential roles in a number of important biological processes (Ahmed et al, 2014;Chen et al, 2018;Doring et al, 2014;Edderkaoui, 2017;Janssens et al, 2018;Ridiandries et al, 2018;Sokol and Luster, 2015;Turner et al, 2014), including hematopoiesis (Wright et al, 2002;Youn et al, 2000) and cancer metastasis (Agarwal et al, 2019;Amedei et al, 2013;Bridge et al, 2018;Chow and Luster, 2014;King et al, 2017;Marcuzzi et al, 2018;Nagarsheth et al, 2017). Because of its clearly demonstrated essential roles for hematopoiesis, CXCL12 is one of the most intensely studied CXC subfamily chemokine factor in the bone marrow (BM) niche (Abe-Suzuki et al, 2014;Aurrand-Lions and Mancini, 2018;Broxmeyer and Kim, 1999;Lewellis and Knaut, 2012;Sugiyama et al, 2006). During development, CXCL12 is essential for efficient migration of hematopoietic stem cells (HSCs) from the fetal liver, the primary hematopoietic organ during late-gestation mammalian development, to the BM, the main site of post-birth hematopoiesis (Ara et al, 2003;Christensen et al, 2004).…”