Impact of a novel prognostic model on allogeneic hematopoietic stem cell transplantation outcomes in patients with CMML.

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell malignancy, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curable treatment. The outcomes after transplant are influenced by both disease characteristics and patient comorbidities. To develop a novel prognostic model to predict the post-transplant survival of CMML patients, we identified risk factors by applying univariable and multivariable Cox proportional hazards regression to a derivation cohort. In multivariable analysis, advanced age (hazard ratio [HR] 3.583), leukocyte count (HR 3.499), anemia (HR 3.439), bone marrow blast cell count (HR 2.095), and no chronic graft versus host disease (cGVHD; HR 4.799) were independently associated with worse survival. A novel prognostic model termed ABLAG (Age, Blast, Leukocyte, Anemia, cGVHD) was developed and the points were assigned according to the regression equation. The patients were categorized into low risk (0-1), intermediate risk (2, 3), and high risk (4-6) three groups and the 3-year overall survival (OS) were 93.3% (95%CI, 61%-99%), 78.9% (95%CI, 60%-90%), and 51.6% (95%CI, 32%-68%; p < .001), respectively. In internal and external validation cohort, the area under the receiver operating characteristic (ROC) curves of the ABLAG model were 0.829 (95% CI, 0.776-0.902) and 0.749 (95% CI, 0.684-0.854). Compared with existing models designed for the nontransplant setting, calibration plots, and decision curve analysis showed that the ABLAG model revealed a high consistency between predicted and observed outcomes and patients could benefit from this model. In conclusion, combining disease and patient characteristic, the ABLAG model provides better survival stratification for CMML patients receiving allo-HSCT.

[Research Progress on the Roles of Rapamycin for the Prophylaxis and Treatment of Graft-Versus-Host Disease --Review].

Graft-versus-host disease (GVHD) reduces the clinical effect and life quality of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Especially for steroid-resistant GVHD, it becomes essential to explore new prevention and treatment strategies. Rapamycin has shown certain clinical advantages in the prevention and treatment of acute and chronic GVHD by inhibiting the mTOR signal pathway. Furthermore, rapamycin exhibits the ability to regulate cell subsets, including T cells, B cell, dendritic cells and myeloidderived suppressor cells, which elucidates the mechanism on effective preventing and treating GVHD. This article reviewed the roles of mTOR inhibitor-rapamycin on GVHD, and discussed how to optimize the usage of rapamycin.

Fabrication of MPEG-b-PMAA capped YVO4:Eu nanoparticles with biocompatibility for cell imaging.

A novel nanoparticle with multilayer core-shell architecture for cell imaging is designed and synthesized by coating a fluorescent YVO4:Eu core with a diblock copolymer, MPEG-b-PMAA. The synthesis of YVO4:Eu core, which further makes MPEG-b-PMAA-YVO4:Eu NPs adapt for cell imaging, is guided by the model determined upon the evaluation of pH and CEu%. The PMAA block attached tightly on the YVO4:Eu core forms the inner shell and the MPEG block forms the biocompatible outermost shell. Factors including reaction time, reaction temperature, CEu% and pH are optimized for the preparation of the YVO4:Eu NPs. A precise defined model is established according to analyzing the coefficients of pH and CEu% during the synthesis. The MPEG-b-PMAA-YVO4:Eu NPs, with an average diameter of 24 nm, have a tetragonal structure and demonstrate luminescence in the red region, which lies in a biological window (optical imaging). Significant enhancement in luminescence intensity by MPEG-b-PMAA-YVO4:Eu NPs formation is observed. The capping copolymer MPEG-b-PMAA improves the dispersibility of hydrophobic YVO4:Eu NPs in water, making the NPs stable under different conditions. In addition, the biocompatibility MPEG layer reduces the cytotoxicity of the nanoparticles effectively. 95% cell viability can be achieved at the NPs concentration of 800 mgL(-1) after 24h of culture. Cellular uptake of the MPEG-b-PMAA-YVO4:Eu NPs is evaluated by cell imaging assay, indicating that the NPs can be taken up rapidly and largely by cancerous or non-cancerous cells through an endocytosis mechanism.

Human umbilical cord blood-derived stromal cells are superior to human umbilical cord blood-derived mesenchymal stem cells in inducing myeloid lineage differentiation in vitro.

Stromal cells and mesenchymal stem cells (MSCs), 2 important cell populations within the hematopoietic microenvironment, may play an important role in the development of hematopoietic stem/progenitor cells. We have successfully cultured human umbilical cord blood-derived stromal cells (hUCBDSCs). It has been demonstrated that MSCs also exist in hUCB. However, we have not found any reports on the distinct characteristics of hUCBDSCs and human umbilical cord blood-derived mesenchymal stem cells (hUCBDMSCs). In this study, hUCBDSCs and hUCBDMSCs were isolated from the cord blood of full-term infants using the same density gradient centrifugation and cultured in the appropriate medium. Some biological characteristics and hematopoietic supportive functions were compared in vitro. hUCBDSCs were distinct from hUCBDMSCs in morphology, proliferation, cell cycle, passage, immunophenotype, and the capacity for classical tri-lineage differentiation. Finally, quantitative real-time polymerase chain reaction analysis revealed that granulocyte colony-stimulating factor (G-CSF) gene expression was higher in hUCBDSCs than that in hUCBDMSCs. Enzyme-linked immunosorbent assay revealed that the secretion of G-CSF, thrombopoietin (TPO), and granulocyte macrophage colony-stimulating factor (GM-CSF) by hUCBDSCs was higher than that by hUCBDMSCs. After coculture, the granulocyte/macrophage colony-forming units (CFU-GM) of hematopoietic cells from the hUCBDSC feeder layer was more than that from the hUCBDMSC feeder layer. Flow cytometry was used to detect CD34(+) hematopoietic stem/progenitor cell committed differentiation during 14 days of coculture; the results demonstrated that CD14 and CD33 expression in hUCBDSCs was significantly higher than their expression in hUCBDMSCs. This observation was also true for the granulocyte lineage marker, CD15. This marker was expressed beginning at day 7 in hUCBDSCs. It was expressed earlier and at a higher level in hUCBDSCs compared with hUCBDMSCs. In conclusion, hUCBDSCs are different from hUCBDMSCs. hUCBDSCs are superior to hUCBDMSCs in supporting hematopoiesis stem/progenitor cells differentiation into myeloid lineage cells at an early stage in vitro.

Cotransplantation of human umbilical cord blood-derived stromal cells enhances hematopoietic reconstitution and engraftment in irradiated BABL/c mice.

Our previous study demonstrated that human umbilical cord blood-derived stromal cells (hUCBDSCs) support the growth of hematopoietic stem cells, and promote the expansion of colony-forming units of megakaryocyte (CFU-Mk) even more efficiently than human bone marrow stromal cells (hBMSCs). Given the unique role of hUCBDSCs in megakaryocytopoiesis in vitro, in this follow up study, we further investigated their effects in vivo on hematopoiesis in the setting of hematopoietic stem cell (HSC) transplants. After infusing hematopoietic cells alone or together with either hUCBDSCs or hBMSCs into lethally irradiated BABL/c mice, we examined the engraftment of human CD45+ cells in the mouse bone marrow with flow cytometry, observed the survival rate of irradiated mice, obtained blood counts and bone marrow biopsies at different time points post-transplant, and assessed colony forming and the homing efficiency of hematopoietic cells. By comparing HSC transplantation with or without stromal cells, we show here that hUCBDSCs efficiently promote the homing of hematopoietic cells to the marrow and enhance the engraftment after cotransplantation. They also promote hematopoietic reconstitution, particularly of the megakaryocytic lineage, and restore the impaired stromal microenvironment after radiation-induced damages. These effects of hUCBDSCs are more potent than those of hBMSCs. In conclusion, our findings suggest the role of hUCBDSCs to facilitate hematopoietic reconstitution and engraftment when cotransplanted with hematopoietic cells.

Human umbilical cord blood-derived stromal cells: multifaceted regulators of megakaryocytopoiesis.

It has been demonstrated that stromal cell precursors exist in human umbilical cord blood. After being cultured in vitro, these cells are called human umbilical cord blood-derived stromal cells (hUCBDSCs). However, the role of hUCBDSCs in hematopoiesis is still unclear. We have previously shown that hUCBDSCs are superior to human bone marrow stromal cells (hBMSCs) at enhancing the expansion of megakaryocyte colony forming units (CFU-Meg). Based on this observation, we postulated that hUCBDSCs might promote megakaryocytopoiesis. to test this hypothesis, we developed a megakaryocyte/hUCBDSC co-culture model and a hematopoietic microenvironment injury model in nude mice. We explored the ability and mechanisms by which hUCBDSCs promoted the proliferation of megakaryocytes in vitro, and we also explored their capacity to restore the hematopoietic microenvironment in vivo. As expected, hUCBDSCs were more efective than hBMSCs at enhancing the proliferation of megakaryocyte lines from HeL cells and restoring megakaryocytopoiesis in a hematopoietic microenvironment injury model in nude mice. thrombopoietin (tpo) and stromal cell derived factor-1 (SDF-1) are two of the key factors underlying this capacity. We also found that gap junction intercellular communication (GJIC) between HeL cells and hUCBDSCs might be partially absent. our data provide the first evidence that hUCBDSCs play a regulatory role during megakaryocytopoiesis, which might be important for designing treatments for patients with megakaryocytic injury.