Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system. Umbilical cord derived mesenchymal stem cells are immunosuppressive. We transplanted mesenchymal stem cells in a patient with refractory progressive MS, and the disease course was stabilized after the transplantation. We postulate that mesenchymal stem cells have a potent immunosuppressive effect in vivo.

Our previous data have revealed that proteinuria, antinuclear antibodies and anti-dsDNA antibodies in refractory systemic lupus erythematosus (SLE) reduced after MSC infusion. This study focused on the roles of mesenchymal SCT (MSCT) in SLE patients with refractory cytopenia. Thirty-five SLE patients with refractory cytopenia were enrolled in a MSCT trial. Hematological changes of pre-and post-transplantation were evaluated. Mechanisms for MSCT effects focused on the analysis of percentage of regulatory T cells (Treg) and Th17. The results showed that in 35 SLE patients, 20 patients had leukopenia, 24 with anemia or thrombocytopenia. The average follow-up period after MSCT was 21 months (range 6-45 months). Significant improvements in blood cell count were found after MSCT for most patients, in parallel with the decline of disease activity. Clinical remission was accompanied by increased Treg and decreased Th17. Two patients died of uncontrolled disease recurrence after infection, whereas no adverse events related to transplantation was observed. The result suggested that MSCT could reverse hematological aberration in SLE patients with refractory cytopenia, which might be associated with reconstitution of Treg and Th17. Longer follow-up and clinical larger-scale controlled study, as well as the exact mechanism exploration, will need further investigations.

The ‘Yamanaka factors' (Oct4, Sox2, Klf4 and c-Myc) are able to generate induced pluripotent stem (iPS) cells from different cell types. However, to what degree primary malignant cells can be reprogrammed into a pluripotent state has not been vigorously assessed. We established an acute myeloid leukemia (AML) model by overexpressing the human mixed-lineage leukemia-AF9 (MLL-AF9) fusion gene in mouse hematopoietic cells that carry Yamanaka factors under the control of doxycycline (Dox). On addition of Dox to the culture, the transplantable leukemia cells were efficiently converted into iPS cells that could form teratomas and produce chimeras. Interestingly, most chimeric mice spontaneously developed the same type of AML. Moreover, both iPS reprogramming and leukemia reinitiation paths could descend from the same leukemia-initiating cell. RNA-seq analysis showed reversible global gene expression patterns between these interchangeable leukemia and iPS cells on activation or reactivation of MLL-AF9, suggesting a sufficient epigenetic force in driving the leukemogenic process. This study represents an important step for further defining the potential interplay between oncogenic molecules and reprogramming factors during MLL leukemogenesis. More importantly, our reprogramming approach may be expanded to characterize a range of hematopoietic malignancies in order to develop new strategies for clinical diagnosis and treatment.

Background:CD44, a transmembrane glycoprotein expressed in a variety of cells and tissues, has been implicated in tumour metastasis. But the molecular mechanisms of CD44-mediated tumour cell metastasis remain to be elucidated.Methods:The downregulation of CD44 was determined by immunofluorescence. Moreover, the motility of breast cancer cells was detected by wound-healing and transwell experiments. Then the spontaneous metastasis of CD44-silenced MDA-MB-231 cells was tested by histology with BALB/c nude mice.Results:A positive correlation between CD44 and Na+/H+ exchanger isoform 1 (NHE1) was found in two breast cancer cells. CD44 downregulation could inhibit the metastasis of MDA-MB-231 cells and the expressions of Na+/H+ exchanger 1. Moreover, CD44 overexpression upregulated the metastasis of MCF-7 cells, but the elevated metastatic ability was then inhibited by Cariporide. Interestingly, during these processes only the p-ERK1/2 was suppressed by CD44 downregulation and the expression of matrix metalloproteinases and metastatic capacity of MDA-MB-231 cells were greatly inhibited by the MEK1 inhibitor PD98059, which even had a synergistic effect with Cariporide. Furthermore, CD44 downregulation inhibits breast tumour outgrowth and spontaneous lung metastasis.Conclusions:Taken together, this work indicates that CD44 regulates the metastasis of breast cancer cells through regulating NHE1 expression, which could be used as a novel strategy for breast cancer therapy.

Leukemia often results in severe anemia, which may significantly contribute to patient mortality and morbidity. However, the mechanisms underlying defective erythropoiesis in leukemia have not been fully elucidated. In this study, we demonstrated that insufficient erythropoiesis in an immunocompetent acute myeloid leukemia (AML) murine model was due to reduced proliferation of megakaryocyte erythroid progenitors and increased apoptosis of erythroblasts. Colony-forming cell assays indicated that the leukemic bone marrow (BM) plasma inhibited erythroid colony formation, whereas they had no inhibitory effect on other types of colonies. Cytokine array analysis demonstrated that the chemokine CCL3 was elevated in the plasma of AML mice and patients. CCL3 inhibited erythroid differentiation of hematopoietic stem cells, common myeloid progenitors and especially megakaryocytic-erythroid progenitors. Administration of the CCR1 antagonist partially recovered the yield of erythroid colonies in the presence of CCL3 or leukemic BM plasma. Mechanistically, we observed an increase of p38 phosphorylation and subsequent downregulation of GATA1 after CCL3 treatment. Furthermore, knockdown of CCL3 attenuated leukemic progression and alleviated anemia. Therefore, our results demonstrate that elevated CCL3 in the leukemic environment suppresses erythropoiesis via CCR1-p38 activation, suggesting a novel mechanism for the erythroid defects observed in leukemia.

Background This study aimed to investigate the effect of typhaneoside on ventricular remodeling and regulation of the PI3K/Akt/mTOR autophagy transduction pathway in rats with heart failure after myocardial infarction. Methods The effects of typhaneoside on the general condition of rats were observed in vivo using a rat model of heart failure after myocardial infarction had been established. The expression of serum N‑terminal pro-brain natriuretic peptide (NT-proBNP), matrix lysin 2 (ST2), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), matrix metalloproteinase 2 (MMP-2), and MMP-9 was detected via ELISA. A hypoxia/reoxygenation model was established to analyze the number and morphology of autophagosomes in vitro by transmission electron microscopy. Light chain 3 (LC3) variations were detected by immunofluorescence. Western blotting was used to assess LC3-II/LC3-I and p62 expression as well as p‑Akt/Akt, p‑mTOR/mTOR ratios. Results Compared with the sham group, the general condition scores of the rats in the model group decreased significantly, while the expression of serum NT-proBNP, ST2, IL-6, TNF-α, MMP-2, and MMP-9 increased. The number of autophagosomes in the drug-containing serum group was significantly reduced and the ratio of LC3-II/LC3-I was significantly decreased. The expression of P62 protein was increased, and the ratios of p‑Akt/Akt and p‑mTOR/mTOR were significantly increased. Conclusion Typhaneoside regulates IL-6 and TNF-α as well as MMP-2 and MMP-9 in rats with heart failure after myocardial infarction. Typhaneoside can improve cardiac morphological structure and myocardial remodeling and enhance heart function. It may mediate autophagy inhibition in the cardiomyocyte anoxia/reoxygenation (A/R) pathway through the PI3K/Akt/mTOR autophagy transduction pathway.

Tuberous sclerosis complex 1 (TSC1) and TSC2 are suppressors of mechanistic target of rapamycin (mTOR). mTOR is the major component of two protein complexes: mTOR complex 1 (mTORC1) and mTORC2. Inactive mutation of either TSC1 or TSC2 unleashes mTOR signaling and consequently causes TSC, a benign tumor syndrome affecting multiple organs. We report here that expression of αB-crystallin was upregulated in Tsc1-/- or Tsc2-/- mouse embryonic fibroblasts, Eker rat uterine leiomyoma-derived Tsc2-deficient ELT3 cells, mutant Tsc2-associated mouse kidney tumors, and human lung lymphangioleiomyomatosis nodules. αB-crystallin was transcriptionally activated by mTOR complex 2 (mTORC2): nuclear factor-kappa B (NFκB) signaling cascade. The augmented αB-crystallin was critical for the migration, invasion and apoptotic resistance of Tsc2-defective cells. Disruption of αB-crystallin suppressed Tsc2-null cell proliferation and tumorigenesis. Therefore, enhanced αB-crystallin has an essential role in TSC1/2 complex deficiency-mediated tumorigenesis, and inhibition of αB-crystallin may complement the current therapy for TSC.

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