Mesenchymal stem cells are functionally abnormal in patients with immune thrombocytopenic purpura

Pérez-Simón, Josè Antonio; Tabera, Soraya; Sarasquete, María Eugenia; Díez-Campelo, María; Canchado, Javier; Sánchez‐Abarca, Luis Ignacio; Blanco, Belén; Alberca, Ignacio; Herrero-Sánchez, Carmen; Cañizo, Consuelo del; Miguel, Jesús San

doi:10.1080/14653240903051558

Cited by 18 publications

(37 citation statements)

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“…44 In this study, we demonstrated that MSCs from ITP patients had a lower proliferative capacity, which was consistent with previous reports. 10 When treated with THD, their apoptosis decreased significantly and more cells entered into S 1 G2 phase. To further identify the underlying mechanisms involved in these changes, we first analyzed the gene-expression profile of MSCs modulated by THD using microarray.…”

Section: Discussionmentioning

confidence: 99%

“…Differentially expressed genes indexed by Gene Ontology (Go) biological process of MSCs were shown in the Gene Expression Omnibus database under accession number GSE44948; enrichment for variants was associated with DNA-dependent regulation of transcription, cell cycle, mitosis, DNA replication, cell proliferation, apoptosis, regulation of cell growth, and regulation of apoptosis, etc. Combining with previous research, 10,[30][31][32] we selected several genes associated with cell proliferation, apoptosis and cell cycle, including p27, p16, caspase-8, caspase-10, klf4, c-myc, oct3/4, and tgf-b1 which may be associated with THD modulation. As shown in Figure 2A-B, the expression of caspase-8 and caspase-10 was downregulated in THD-MSCs (ITP), while there was no significant difference between MSCs (control) and THD-MSCs (control).…”

Section: Analysis Of Global Gene Expression In Mscs Before and After mentioning

confidence: 99%

“…MSCs were isolated and cultured from BM of ITP patients (MSC [ITP]) and healthy controls (MSC [control]) as previously described, 10 with minor modifications. The MSCs were maintained in MesenPRO RS medium (Invitrogen).…”

Section: Cellsmentioning

confidence: 99%

“…[6][7][8][9] Recently, Perez-Simon et al found impaired proliferative and functional capacity of mesenchymal stem cells (MSCs) in patients with ITP. 10 Although a low dose of dexamethasone favors MSC expansion in vitro, it could impair immunosuppression of MSCs on peripheral blood mononuclear cells (PBMCs). 11 It is not suitable for MSCs to be pretreated with dexamethasone when they are to be used to treat immunologic disease.…”

Section: Introductionmentioning

confidence: 99%

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Thalidomide corrects impaired mesenchymal stem cell function in inducing tolerogenic DCs in patients with immune thrombocytopenia

Ning

et al. 2013

Blood

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Section: Discussionmentioning

confidence: 99%

Section: Analysis Of Global Gene Expression In Mscs Before and After mentioning

confidence: 99%

Section: Cellsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Thalidomide corrects impaired mesenchymal stem cell function in inducing tolerogenic DCs in patients with immune thrombocytopenia

Ning

et al. 2013

Blood

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“…We have previously reported that patients with immune thrombocytopenic purpura had functional abnormalities in MSCs, which may influence the physiopathology of the disease and could support the use of MSCs for the treatment of these patients. 21 In conclusion, the current study is the first clinical trial to evaluate the feasibility and safety of MSCs expanded in vitro using autologous serum for the treatment of acute and chronic GVHD. In terms of MSC expansion, this procedure yields enough cells in most cases, although the addition of platelet lysate may improve the growth kinetics.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells expanded in vitro with human serum for the treatment of acute and chronic graft-versus-host disease: results of a phase I/II clinical trial

Pérez-Simón¹,

López-Villar²,

Andreu³

et al. 2011

Haematologica

157

105

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MSC expansion procedure, cell characterization and obtaining platelet lysate were performed according to standard procedures and are shown in the Online Supplementary Appendix. Patients' characteristics and MSC infusionOverall, 18 patients diagnosed with either acute (n=10) or chronic (n=8) GVHD refractory to prior treatment were included in the study once written informed consent had been obtained. Refractory GVHD was defined as progression or absence of response to last treatment. Patients' characteristics are summarized in Table 2. Eleven patients had received reduced intensity conditioning and 6 received myeloablative conditioning. Fourteen patients had received hematopoietic stem cells from an unrelated donor and 7 received them from an HLA-mismatched donor. Eight patients had received GVHD prophylaxis based on a calcineurin inhibitor plus methotrexate.Inclusion criteria were: patients who had undergone an allogeneic stem cell transplant and developed GVHD refractory to conventional treatment; adequate cardiac and pulmonary functions; aged between 18 and 65 years; signed informed consent from patient and donor. Exclusion criteria were: patients who did not fulfill all of the inclusion criteria; progression of the hematologic disease; active infection; women who were either pregnant or at risk of pregnancy. The study was conducted between February 2007 and December 2009.Patients received 1-2x10 6 MSCs/kg intravenously in a single dose. Eventually, when a partial response was obtained or in the case of relapse after achieving complete remission, patients could receive a second dose of MSCs at least two weeks after the first infusion. Patients who were receiving 6-methylprednisolone were kept on the same doses for at least seven days after MSC infusion and a taper of 10% every five days was planned later when there was a response. Other immunosuppressive drugs were managed according to the criteria of the attending physician. Response to therapy was measured according to previously reported criteria. [9][10][11] Patients were taken off the study if fewer than 1x10 6 MSCs/kg were obtained after eight weeks of expansion. All patients receiving at least one dose of MSCs were included in the safety and efficacy analysis.The treatment protocol was reviewed and approved by the local authorities and ethical committee of all participanting centers.Mesenchymal cells for graft vs. host disease treatment haematologica | 2011; 96 (7) 1073 Statistical analysisVariables of the expansion procedure were analyzed from the day of inclusion in the trial, i.e. the day when informed consent was signed. Mean and median values and their corresponding 95% confidence intervals (CIs) and ranges were calculated for each continuous variable. Student's two-sample t test and Pearson's X 2 test were used to compare continuous and qualitative variables. In those comparisons where the number of cases precluded the use of parametric tests, the Mann-Whitney test and Fisher's exact test were used. To analyze patient outcome after infusi...

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Imbalance Between Bone Morphogenetic Protein 2 and Noggin Induces Abnormal Osteogenic Differentiation of Mesenchymal Stem Cells in Ankylosing Spondylitis

Xie

Wang

et al. 2016

Arthritis & Rheumatology

117

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Objective. To study the osteogenic differentiation capacity of bone marrow-derived mesenchymal stem cells (BM-MSCs) from patients with ankylosing spondylitis (AS) and to investigate the mechanisms of abnormal osteogenic differentiation of BM-MSCs in AS.Methods. BM-MSCs from healthy donors (HDMSCs) and patients with AS (AS-MSCs) were cultured in osteogenic differentiation medium for 0-21 days, after which their osteogenic differentiation capacity was determined using alizarin red S and alkaline phosphatase assays. Gene expression levels of osteoblastic markers and related cytokines were detected by high-throughput quantitative reverse transcription-polymerase chain reaction. Enzyme-linked immunosorbent assay was performed to detect protein levels of bone morphogenetic protein 2 (BMP-2) and Noggin in the cell culture supernatant. The activation of Smad1/5/8 and MAPK signaling pathways was measured by Western blotting. The balance between BMP-2 and Noggin expression was regulated using lentiviruses encoding short hairpin RNA and exogenous Noggin, respectively, which enabled evaluation of how this balance affected osteogenic differentiation of AS-MSCs.Results. AS-MSCs outperformed HD-MSCs in osteogenic differentiation capacity. During osteogenic differentiation, AS-MSCs secreted more BMP-2 but less Noggin, accompanied by an overactivation of Smad1/5/ 8 and ERK-1/2. When the Noggin concentration was increased or BMP-2 expression was inhibited, the abnormal osteogenic differentiation of AS-MSCs was rectified. In addition, the balance between BMP-2 and Noggin secretion was restored.Conclusion. The results of this study demonstrate that an imbalance between BMP-2 and Noggin secretion induces abnormal osteogenic differentiation of AS-MSCs. These findings reveal a mechanism of pathologic osteogenesis in AS and provide a new perspective on inhibiting pathologic osteogenesis by regulating the balance between BMP-2 and Noggin.

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Mesenchymal stem cells are functionally abnormal in patients with immune thrombocytopenic purpura

Cited by 18 publications

References 0 publications

Thalidomide corrects impaired mesenchymal stem cell function in inducing tolerogenic DCs in patients with immune thrombocytopenia

Thalidomide corrects impaired mesenchymal stem cell function in inducing tolerogenic DCs in patients with immune thrombocytopenia

Mesenchymal stem cells expanded in vitro with human serum for the treatment of acute and chronic graft-versus-host disease: results of a phase I/II clinical trial

Imbalance Between Bone Morphogenetic Protein 2 and Noggin Induces Abnormal Osteogenic Differentiation of Mesenchymal Stem Cells in Ankylosing Spondylitis

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