Effects of FGF21-secreting adipose-derived stem cells in thioacetamide-induced hepatic fibrosis.
J Cell Mol Med. 2018 Jul 18;:
Authors: Kang H, Seo E, Park JM, Han NY, Lee H, Jun HS
Mesenchymal stem cells (MSCs) have been investigated to treat liver diseases, but the efficiency of MSCs to treat chronic liver diseases is conflicting. FGF21 can reduce inflammation and fibrosis. We established FGF21-secreting adipose derived stem cells (FGF21_ADSCs) to enhance the effects of ADSCs and transplanted them into thioacetamide (TAA)-induced liver fibrosis mice via the tail vein. Transplantation of FGF21_ADSCs significantly improved liver fibrosis by decreasing serum hyaluronic acid and reducing the expression of fibrosis-related factors such as α-smooth muscle actin (α-SMA), collagen and tissue inhibitor of metalloproteinase-1 (TIMP-1) compared with the Empty_ADSCs by inhibition of p-JNK, NF-κB and p-Smad2/3 signalling. α-lactoalbumin (LA) and lactotransferrin (LTF), secretory factors produced from FGF21_ADSCs inhibited TGF-β1-induced expression of α-SMA and collagen in LX-2 cells. These results suggest that transplantation of FGF21_ADSCs inhibited liver fibrosis more effectively than Empty_ADSCs, possibly via secretion of α-LA and LTF.
PMID: 30019838 [PubMed - as supplied by publisher]
The lentiviral-mediated Nurr1 genetic engineering mesenchymal stem cells protect dopaminergic neurons in a rat model of Parkinson's disease.
Am J Transl Res. 2018;10(6):1583-1599
Authors: Wang X, Zhuang W, Fu W, Wang X, Lv E, Li F, Zhou S, Rausch WD, Wang X
Nuclear receptor-related factor 1 (Nurr1) has a crucial role in the development and maturation of mesencephalic dopamine (DA) neurons and also plays a protective role in maintenance of DA neurons by inhibiting the activation of microglia and astrocyte. Moreover, the mutations in Nurr1 gene are associated with familial Parkinson's disease (PD), suggested that Nurr1 modulation is a potential therapeutic target for PD. This study examines the therapeutic effects of transplantation of Nurr1 gene-modified bone marrow mesenchymal stem cells (MSCs) on 6-hydroxydopamine (6-OHDA)-induced PD rat models. MSCs were transduced with lentivirus expressing Nurr1 gene and then intrastriatally transplanted into PD rats. Our results showed that Nurr1 gene-modified MSCs overexpress and secrete Nurr1 protein in vitro and also survive and migrate in the brain. Four weeks after transplantation Nurr1 gene-modified MSCs dramatically ameliorated the abnormal behavior of PD rats and increased the numbers of tyrosine hydroxylase (TH)-positive cells in the substantia nigra (SN) and TH-positive fibers in the striatum, inhibited the activation of glial cells, and reduced the expression of inflammatory factors in the SN. Taken together, these findings suggest that intrastriatal transplantation of lentiviral vector mediated Nurr1 gene-modified MSCs has notable therapeutic effect for PD rats.
PMID: 30018702 [PubMed]
Therapy-related acute myeloid leukemia developing 14 years after allogeneic hematopoietic stem cell transplantation, from a persistent R882H-DNMT3A mutated clone of patient origin.
Exp Mol Pathol. 2018 Jul 11;:
Authors: Martín I, Navarro B, Villamón E, Solano C, Serrano A, Calabuig M, Amat P, Domingo F, Abellán R, García F, Olivares MD, Chaves FJ, Tormo M, Hernández-Boluda JC
BACKGROUND: Therapy-related acute myeloid leukemia (t-AML) develops in patients with prior exposure to cytotoxic therapies. Selection of a pre-existing TP53 mutated clone prone to acquire additional mutational events has been suggested as the main pathogenic mechanism of t-AML. Here, we report a unique case of t-AML which developed from a pre-existing DNMT3A mutated clone that persisted in the patient for more than 10 years despite treatment with intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (alloHSCT).
CASE PRESENTATION: A 42-year-old male was diagnosed with AML harboring a normal karyotype and mutations in the NPM1 (c.863_864ins, p.W288 fs*12), DNMT3A (c.2645G > A, p.R882H), and IDH1 (c.395G > A, p.R132H) genes. He achieved complete remission with intensive chemotherapy and was subsequently submitted to alloHSCT. Eleven years later, he was given chemotherapy and radiotherapy to treat a lung carcinoma. Three years later, t-AML was diagnosed; the disease had arisen from a pre-existing DNMT3A mutated patient-origin clone that had subsequently acquired a TP53 mutation and a complex karyotype. Although a second transplantation was intended, the disease was refractory to induction chemotherapy, and the patient eventually died from disease complications. We retrospectively demonstrated the persistence and post-transplantation latency of the R882H-DNMT3A mutation using a real-time PCR allele-specific analysis at different time-points during the observation period.
DISCUSSION AND CONCLUSION: The present case highlights the potential clinical implications of a R882H-DNMT3A mutated clone that persisted after conventional AML treatment, including alloHSCT. It also reinforces the notion of the importance of cell non-intrinsic factors, such as the hematopoietic-stress induced by chemotherapy and radiotherapy, as drivers of clonal expansion.
PMID: 30017658 [PubMed - as supplied by publisher]
Effect of pre-transplantation serum ferritin on outcomes in patients undergoing allogeneic hematopoietic stem cell transplantation: A meta-analysis.
Medicine (Baltimore). 2018 Jul;97(27):e10310
Authors: Yan Z, Chen X, Wang H, Chen Y, Chen L, Wu P, Wang W
BACKGROUND: Pre-transplantation serum ferritin (SF) has been considered to be a potential prognostic biomarker in patients undergoing allogeneic hematopoietic stem cell transplantation (allogeneic HSCT), but this conclusion remains controversial. Thus, we performed a meta-analysis to investigate the prognostic significance of pre-transplantation SF in patients undergoing allogeneic HSCT.
METHODS: We systematically searched PubMed, Embase, and Web of Science up to September 2017, and finally identified a total of 25 eligible studies with 4545 patients.
RESULTS: The pooled results of our meta-analysis showed that high pre-transplantation SF was markedly related to worse overall survival (OS) [hazard ratio (HR) = 1.82; 95% confidence interval (95% CI): 1.47-2.26; P < .001], nonrelapse mortality (NRM) (HR = 2.28; 95% CI: 1.79-2.89; P < .001), and progression-free survival (PFS) (HR = 1.72; 95% CI: 1.27-2.33; P < .001). In addition, high pre-transplantation SF was closely associated with a lower incidence of chronic graft versus host disease (cGVHD) (OR = 0.74, 95% CI: 0.58-0.96; P < .05), and a higher incidence of blood stream infections (BSIs) (OR = 1.67, 95% CI: 0.93-3.01; P = .09). However, no significance relationship was found between elevated pre-transplantation SF and acute graft versus host disease (aGVHD) (OR = 1.08, 95% CI:.72-1.62; P = .70).
CONCLUSION: In patients undergoing allogeneic HSCT for hematological malignancies, elevated pre-transplantation SF was significantly associated with worse OS and PFS, higher incidence of NRM and BSI, and lower incidence of cGVHD, but it had no effect on aGVHD. Considering the limitations in our meta-analysis, more prospective and homogeneous clinical studies are needed to further confirm our findings.
PMID: 29979374 [PubMed - indexed for MEDLINE]
Low-level laser irradiation at a high power intensity increased human endothelial cell exosome secretion via Wnt signaling.
Lasers Med Sci. 2018 Jul;33(5):1131-1145
Authors: Bagheri HS, Mousavi M, Rezabakhsh A, Rezaie J, Rasta SH, Nourazarian A, Avci ÇB, Tajalli H, Talebi M, Oryan A, Khaksar M, Kazemi M, Nassiri SM, Ghaderi S, Bagca BG, Rahbarghazi R, Sokullu E
The distinct role of low-level laser irradiation (LLLI) on endothelial exosome biogenesis remains unclear. We hypothesize that laser irradiation of high dose in human endothelial cells (ECs) contributes to the modulation of exosome biogenesis via Wnt signaling pathway. When human ECs were treated with LLLI at a power density of 80 J/cm2, the survival rate reduced. The potential of irradiated cells to release exosomes was increased significantly by expressing genes CD63, Alix, Rab27a, and b. This occurrence coincided with an enhanced acetylcholine esterase activity, pseudopodia formation, and reduced zeta potential value 24 h post-irradiation. Western blotting showed the induction of LC3 and reduced level of P62, confirming autophagy response. Flow cytometry and electron microscopy analyses revealed the health status of the mitochondrial function indicated by normal ΔΨ activity without any changes in the transcription level of PINK1 and Optineurin. When cells exposed to high power laser irradiation, p-Akt/Akt ratio and in vitro tubulogenesis capacity were blunted. PCR array and bioinformatics analyses showed the induction of transcription factors promoting Wnt signaling pathways and GTPase activity. Thus, LLLI at high power intensity increased exosome biogenesis by the induction of autophagy and Wnt signaling. LLLI at high power intensity increases exosome biogenesis by engaging the transcription factors related to Wnt signaling and autophagy stimulate.
PMID: 29603107 [PubMed - indexed for MEDLINE]
Analysis of factors affecting initial cyclosporine level and its impact on post transplant outcomes in acute leukemia.
J Cancer Res Ther. 2017 Oct-Dec;13(6):981-988
Authors: Gupta A, Punatar S, Gawande J, Mathew L, Kannan S, Khattry N
BACKGROUND: Trough cyclosporine (CsA) blood level can influence incidence of graft-versus-host disease (GVHD) and relapse in patients with acute leukemia undergoing allogeneic hematopoietic stem cell transplant (HSCT). We sought to determine factors affecting initial trough CsA level (CsA-1) and its impact on transplant outcome in acute leukemia.
MATERIALS AND METHODS: Seventy-seven patients underwent HSCT for acute leukemia between January 2008 and March 2013 and were included. GVHD prophylaxis included CsA + methotrexate. (MTX) in 53 patients and CsA + mycophenolate mofetil (MMF) in 24 patients CsA-1 was measured on day 3-5 of starting CsA and subsequent dose was modified to achieve therapeutic level of 150-200. ng/mL. According to CsA-1, patients were divided into three groups - 27 in Group A (dose escalated), 13 in Group B (dose de-escalated), and 37 in Group C (same dose continued).
RESULTS: On univariate analysis, cyclophosphamide with total-body irradiation (TBI) based conditioning regimen and lower body mass index (BMI) were associated with lower CsA-1, while use of fludarabine and higher BMI were associated with higher CsA-1. On multivariate analysis, only fludarabine use and BMI affected CsA-1. Incidence of acute and chronic GVHD (aGVHD and cGVHD), transplant-related mortality, relapse incidence, and relapse-free and overall survival (OS) were similar in the three groups.
CONCLUSION: While fludarabine use in conditioning regimen and higher BMI leads to higher CsA-1, transplant outcomes are not affected by CsA-1.
PMID: 29237963 [PubMed - indexed for MEDLINE]