scholarly journals Osteogenic/Adipogenic Imbalance in Bone Marrow Nestin+ mesenchymal Stem Cells in Patients with Chronic Graft-Versus-Host Disease

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5007-5007
Author(s):  
Hanzhou Qi ◽  
Haiyan Zhang ◽  
Kaibo Yang ◽  
Yanqiu Chen ◽  
Hua Jin ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Adipogenic Differentiation ◽  
Bone Marrow Niche ◽  
Host Disease ◽  
Differentiation Capacity ◽  
Relative Expression ◽  
Graft Versus Host

Background: Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The roles of bone marrow niche in cGVHD pathogenesis have gained increasing attention in recent years. Nestin+ mesenchymal stem cells (MSCs) is an important component of bone marrow niche. However, the potential implication of Nestin+ MSCs in the pathophysiology of cGVHD has not been completely clarified. Methods: A total of 68 patients with hematologic malignancies who underwent allo-HSCT at Nanfang Hospital between April 2016 and October 2018 were enrolled in this experimental study. We analyzed expanded Nestin+ MSCs from patients with cGVHD and compared them with patients without cGVHD. The diagnosis and grade of cGVHD was made at the time of sample collection according to National Institutes of Health criteria (Howard M.S. et. al. BBMT 2015). The results were compared using one-way ANOVA and unpaired two-tailed Student t-test. Statistical significance was defined as P value of <.05. Result: The Nestin+ MSCs from both groups showed similar morphology, immunophenotype, proliferation, and apoptosis. However, the adipogenic differentiation capacity of Nestin+ MSCs in patients with cGVHD was significantly reduced compared with patients without cGVHD (relative expression of PPARγ 2.22±0.27, and 6.82±0.87, respectively, P<0.05). The osteogenic differentiation capacity was significantly increased in patients with cGVHD (relative expression of RUNX2 3.84±0.38, and 1.95±0.52, respectively, P<0.05)(Figure 1A,B). These abnormal differentiations were more significant in patients with moderate/severe cGVHD. Furthermore, β-catenin phosphorylation decreased and nuclear β-catenin increased in the Nestin+ MSCs of cGVHD patients(Figure 1 C). Conclusion: These results demonstrate that Nestin+ MSCs from cGVHD patients had abnormal differentiation characterized by decreased adipogenic differentiation capacity and enhanced osteogenic capacity. The reduction of phosphorylation of β-catenin play an important role in these abnormal differentiations. Disclosures No relevant conflicts of interest to declare.

Rat Bone Marrow Mesenchymal Stem Cells Cotransplanted with BM Improve Hematopietic Reconstitution and Immunoreconstitution with Alleviating Graft-versus-Host Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4248-4248
Author(s):  
Jun-xia Lei ◽  
Shu-nong Li ◽  
Xiu-ming Zhang ◽  
Xin Du ◽  
Peng Xiang
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Histological Analysis ◽  
Host Disease ◽  
Graft Versus Host ◽  
Hematopoietic Reconstitution ◽  
Marrow Mesenchymal Stem Cells ◽  
Rat Bone

Abstract Prolonged immunodeficiency after allogeneic bone marrow transplantation (BMT) causes significant morbidity and mortality from infection, while graft versus host disease (GVHD) after allogeneic BMT and immunosuppression therapies against GVHD further deteriorate this process. Adult bone marrow mesenchymal stem cells (MSC) have recently been shown to inhibit T-cell proliferation and reduce GVHD after allo-BMT. In this study, we characterized the effect of MSC on immunoreconstitution and hematopoietic-reconstitution after bone marrow transplantation. BMT model from Fischer344 rats (RT-1Al) to WF rats (RT-1Au) was established for this experiment. Effects of MSCs on hematopoietic reconstitution, immunoreconstitution and GVHD were studied by survival rate, peripheral blood counts, histological analysis and FACS at day +30 after transplantation. Immune function recovery were assessed by lymphocyte proliferation reaction stimulated with ConA and LPS and allogeneic mixed-lymphocyte reaction. At day 30 postransplant, compared with BMT groups, we observed that cotransplantation of MSC and bone marrow promoted the recovery of peripheral blood white blood cells (5.47±1.11x109/L vs7.12±1.70x109/L, p<0.05), lymphocytes and platelets. Accordingly, it was noticed that cotransplantation of MSC with BM not only improved recovery of bone marrow cellularity, but also enhanced B lymphopoiesis (4.66±1.03x109/L vs 6.05±1.39x109/L, p<0.05) and megakaryocytopoiesis (402.50±63.70 x109/L vs 594.33±121.09x109/L, p<0.05). MSC was also shown to improve thymic and spenic architecture reconstitution. Histological analysis showed that near normal thymus architecture and normal spenic architecture, with well-developed red and white pulp and intact lymphoid follicles in the cotransplantation group, while loss of demarcation between cortex and medulla in the thymus and lymphocytic depletion of spenic arteriolar sheaths in BM transplantation rats.The total number of thymus cells and spleen cells were also increased in cotransplantation group compared to only BM transplantation group. Most notable, the higher percentage of CD3+CD4+ was observed in the spleens of cotransplantation group (11.47±3.68% vs 19.14±4.03%, respectively), while no difference in the percentage of CD3+CD8+ between two groups (10.61±3.37% vs 12.13±2.27%, respectively). So the ratio of CD4+/CD8+ cells increased and inclined to normal in cotransplantation groups compared to only BM transplantation group.There are no difference in the percentage of natural killer (NK) cells and monocytes between BMT group and BMT with MSC group. The immuno-inhibitory effect of MSC on reducing GVHD in recipients of an MHC-mismatched BMT was also evident in our study, nonetheless, splenic cells from recipients of MSC cotransplantation group displayed improved non-specific proliferation capability (against ConA LPS stimulation) and alloreactivity (against the third party splenocytes) compared to BM transplantation group. In conclusion, rat bone marrow mesenchymal stem cells cotransplanted with BM improves hematopietic reconstitution and immunoreconstitution with alleviating graft-versus-host disease.

scholarly journals Wnt/β-catenin signaling mediates the abnormal osteogenic and adipogenic capabilities of bone marrow mesenchymal stem cells from chronic graft-versus-host disease patients

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Han-zhou Qi ◽  
Yi-ling Ye ◽  
Yuan Suo ◽  
Hong Qu ◽  
Hai-yan Zhang ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Underlying Mechanism ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Ppar Γ ◽  
Marrow Mesenchymal Stem Cells

AbstractChronic graft-versus-host disease (cGVHD) is the main cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Mesenchymal stem cells (MSCs) in bone marrow (BM) remain unclear in the pathophysiology of cGVHD. In this study, we analyzed BM-MSCs from 66 patients after allo-HSCT, including 33 with active cGVHD and 33 without cGVHD. BM-MSCs showed similar morphology, frequency, phenotype, and proliferation in patients with or without cGVHD. MSCs from the active cGVHD group showed a decreased apoptosis rate (P < 0.01). Osteogenic capacity was increased while adipogenic capacity was decreased in the active cGVHD MSCs compared with no-cGVHD MSCs. The expressions of osteogenic gene RUNX2 and COL1A1 were higher (P < 0.001) while adipogenic gene PPAR-γ and FABP4 were lower (P < 0.001) in the active cGVHD MSCs than no-cGVHD MSCs. These changes were associated with the severity of cGVHD (P < 0.0001; r = 0.534, r = 0.476, r = −0.796, and r = −0.747, respectively in RUNX2, COL1A1, PPAR-γ, and FABP4). The expression of Wnt/β-catenin pathway ligand Wnt3a was increased in cGVHD-MSCs. The dysfunction of cGVHD-MSCs could be reversed by Dickkopf related protein 1(DKK1) to inhibit the binding of Wnt3a. In summary, the differentiation of BM-MSCs was abnormal in active cGVHD, and its underlying mechanism is the upregulated of Wnt3a through Wnt/β-catenin signaling pathway of MSCs.

Treatment of Intractable Graft-Versus-Host Disease with Bone Marrow Derived Mesenchymal Stem Cells - A Pilot Clinical Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4974-4974 ◽  
Author(s):  
Je-Hwan Lee ◽  
Seong-Jun Choi ◽  
Jung-Hee Lee ◽  
Miee Seol ◽  
Young-Shin Lee ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Ex Vivo ◽  
Performance Status ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host

Abstract Recent studies have shown that mesenchymal stem cells (MSCs) have profound immunomodulatory function, both in vitro and in vivo. There are several reports to treat effectively therapy-resistant graft-versus-host disease (GVHD) using ex vivo expanded MSCs. We performed a pilot clinical trial to treat intractable GVHD with bone marrow derived MSCs. All of 5 patients, 3 males and 2 females, with steroid-refractory GVHD were included in this study. Age range was 27 to 48 years old. Diagnosis of underlying disease was CML in 2, AML in 1, ALL in 1, and MDS in 1. Hematopoietic stem cell (HSC) donor was a sibling in 2 and an unrelated volunteer in 3. The donor of MSCs was a sibling in all patients: two donors were the same to HSC donors, but other three were not. About 20 mL of bone marrow was aspirated from donors and MSCs were cultured ex vivo. After about 3 weeks, MSCs were harvested for the first infusion, and 4 more weeks’ culture was done for the planned second infusion. The infused doses of MSCs were 5.3 to 6.9 x 106/kg for the first infusion and 1.8 to 7.0 x 106/kg for the second infusion. The onset of GVHD was post-transplant day 24 to 191 and the times from the onset of GVHD to the infusion of MSCs were 73 to 2469 days. There were no adverse events related to the infusion of MSCs. Three patients did not show any response to the treatment of MSCs for GVHD and two showed minimal response: transient improvement of jaundice and diarrhea without improvement of skin GVHD lesions in one patient, and improvement of performance status without significant increase of pulmonary function test parameters in another patient with lung involvement of GVHD. There were no significant changes in hemoglobin, and peripheral blood counts of platelets, leukocytes, lymphocytes, CD3+ cells, CD4+ cells, CD8+ cells, NK cells and B cells over 6 months’ period after the infusion of MSCs. Results of our pilot study suggest that the treatment effects of MSCs may be limited in patients with chronic established GVHD. Further studies on MSCs for GVHD should be focused on acute or exacerbated GVHD.

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