Marcellina Mangoni

Diabetes Impairs Hematopoietic Stem Cell Mobilization by Altering Niche Function

Impaired mobilization of hematopoietic stem cells in diabetic mice is due to sympathetic nervous system dysregulation of CXCL12 distribution. Boosting Stem Cell Mobilization Transplantation of hematopoietic stem cells (HSCs) from the bone marrow is a successful approach for treating blood diseases and certain cancers. Usually, the patient’s own (autologous) HSCs are used for transplant, but in some patients, their HSCs cannot be mobilized in sufficient numbers using the growth factor G-CSF (granulocyte colony-stimulating factor) to enable a successful transplant. In a new study, Ferraro and colleagues set out to discover the causes of this poor HSC mobilization. The investigators discovered by analyzing data from a number of bone marrow transplant patients that patients with diabetes showed poorer mobilization of HSCs in response to G-CSF than did those patients who did not have diabetes. The authors then confirmed in mouse models of type 1 and type 2 diabetes that HSCs were poorly mobilized from the bone marrow in response to G-CSF in these mice but not healthy control animals. The authors discovered that there was a defect in the bone marrow microenvironment of the diabetic mice rather than a problem with the HSCs themselves. Specifically, in diabetic (but not control) mice, the researchers observed mislocalization of HSCs in the bone marrow and an increase in the number of perivascular sympathetic nerve fibers in the niche with a concomitant inability of bone marrow mesenchymal stem cells to down-modulate production of the chemokine CXCL12 (a molecule known to mediate HSC localization). Finally, the authors were able to overcome the defect in HSC mobilization using a clinically approved drug called AMD3100 that interrupts the interaction of CXCL12 with its receptor CXCR4. The authors suggest that AMD3100 could be used to boost HSC mobilization in diabetic patients who require a bone marrow transplant. Success with transplantation of autologous hematopoietic stem and progenitor cells (HSPCs) in patients depends on adequate collection of these cells after mobilization from the bone marrow niche by the cytokine granulocyte colony-stimulating factor (G-CSF). However, some patients fail to achieve sufficient HSPC mobilization. Retrospective analysis of bone marrow transplant patient records revealed that diabetes correlated with poor mobilization of CD34+ HSPCs. In mouse models of type 1 and type 2 diabetes (streptozotocin-induced and db/db mice, respectively), we found impaired egress of murine HSPCs from the bone marrow after G-CSF treatment. Furthermore, HSPCs were aberrantly localized in the marrow niche of the diabetic mice, and abnormalities in the number and function of sympathetic nerve termini were associated with this mislocalization. Aberrant responses to β-adrenergic stimulation of the bone marrow included an inability of marrow mesenchymal stem cells expressing the marker nestin to down-modulate the chemokine CXCL12 in response to G-CSF treatment (mesenchymal stem cells are reported to be critical for HSPC mobilization). The HSPC mobilization defect was rescued by direct pharmacological inhibition of the interaction of CXCL12 with its receptor CXCR4 using the drug AMD3100. These data suggest that there are diabetes-induced changes in bone marrow physiology and microanatomy and point to a potential intervention to overcome poor HSPC mobilization in diabetic patients.

Production of Wnt Inhibitors by Myeloma Cells: Potential Effects on Canonical Wnt Pathway in the Bone Microenvironment

Osteoblast impairment occurs within multiple myeloma cell infiltration into the bone marrow. Canonical Wnt signaling activation in osteoprogenitor cells is involved in osteoblast formation through the stabilization of dephosphorylated beta-catenin and its nuclear translocation. The effects of multiple myeloma cells on Wnt signaling in human mesenchymal/osteoprogenitor cells are unclear. In 60 multiple myeloma patients checked, we found that among the Wnt inhibitors, Dickkopf-1 and secreted frizzled-related protein-3 were produced by multiple myeloma cells. However, although multiple myeloma cells or multiple myeloma bone marrow plasma affected expression of genes in the canonical Wnt signaling and inhibited beta-catenin stabilization in murine osteoprogenitor cells, they failed to block the canonical Wnt pathway in human mesenchymal or osteoprogenitor cells. Consistently, Wnt3a stimulation in human osteoprogenitor cells did not blunt the inhibitory effect of multiple myeloma cells on osteoblast formation. Consequently, despite the higher Wnt antagonist bone marrow levels in osteolytic multiple myeloma patients compared with nonosteolytic ones, beta-catenin immunostaining was not significantly different. Our results support the link between the production of Wnt antagonists by multiple myeloma cells and the presence of bone lesions in multiple myeloma patients but show that myeloma cells do not inhibit canonical Wnt signaling in human bone microenvironment.

Osteogenic differentiation of mesenchymal stem cells in multiple myeloma: Identification of potential therapeutic targets

OBJECTIVE Osteogenic differentiation of mesenchymal cells toward osteoprogenitor and osteoblastic cells is tightly regulated by several growth and transcription factors at the molecular level. In this article, we focus on the biological mechanisms involved in the osteoblast inhibition induced by myeloma cells. MATERIALS AND METHODS Current research on the mechanisms regulating myeloma cell and osteoprogenitor cells interactions and on potential therapeutic targets to treat multiple myeloma bone disease is reviewed. RESULTS Runt-related transcription factor 2 is critically involved in this process along with a large number of nuclear coregulators. Wnt signaling has been recently identified as a critical pathway involved in the regulation of osteoblastogenesis. The impairment of osteogenic differentiation in mesenchymal stem cells occurs in multiple myeloma due to the capacity of malignant plasma cells to suppress the osteogenic differentiation of mesenchymal cells either through the cell contact or the release of soluble factors as interleukin-7, hepatocyte growth factor, interleukin-3, and Wnt inhibitors. CONCLUSION Runt-related transcription factor 2 and Wnt pathways could be therapeutic targets in the treatment of multiple myeloma bone disease to counterbalance the block of osteogenic differentiation induced by multiple myeloma cells.