Phase I study of cord blood transplantation with intrabone marrow injection of mesenchymal stem cells

Goto, Tatsunori; Murata, Makoto; Terakura, Seitaro; Nishida, Tetsuya; Adachi, Yayoi; Ushijima, Yoko; Shimada, Kazuyuki; Ishikawa, Yuichi; Hayakawa, Fumihiko; Nishio, Naomichi; Nishiwaki, Satoshi; Hirakawa, Akihiro; Kato, Kazushige; Takahashi, Yoshiyuki; Kiyoi, Hitoshi

doi:10.1097/md.0000000000010449

Cited by 16 publications

(18 citation statements)

References 29 publications

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“…There is extensive information on the role of MSC to improve the hematopoietic engraftment , and the administration of MSC to improve engraftment is being explored in clinical trials. As MSC may exert some of their effects through the release of EV , there are some preclinical studies that have explored the role of MSC‐EV in the improvement of hematopoiesis after hematopoietic transplantation and to analyze the MSC‐EV influence on CD34 + cells gene expression pattern, altering their survival and promoting their homing to the BM .…”

Section: Discussionmentioning

confidence: 99%

The Incorporation of Extracellular Vesicles from Mesenchymal Stromal Cells Into CD34+ Cells Increases Their Clonogenic Capacity and Bone Marrow Lodging Ability

et al. 2019

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Mesenchymal stromal cells (MSC) may exert their functions by the release of extracellular vesicles (EV). Our aim was to analyze changes induced in CD34 + cells after the incorporation of MSC-EV. MSC-EV were characterized by flow cytometry (FC), Western blot, electron microscopy, and nanoparticle tracking analysis. EV incorporation into CD34 + cells was confirmed by FC and confocal microscopy, and then reverse transcription polymerase chain reaction and arrays were performed in modified CD34 + cells. Apoptosis and cell cycle were also evaluated by FC, phosphorylation of signal activator of transcription 5 (STAT5) by WES Simple, and clonal growth by clonogenic assays. Human engraftment was analyzed 4 weeks after CD34 + cell transplantation in nonobese diabetic/severe combined immunodeficient mice. Our results showed that MSC-EV incorporation induced a downregulation of proapoptotic genes, an overexpression of genes involved in colony formation, and an activation of the Janus kinase (JAK)-STAT pathway in CD34 + cells. A significant decrease in apoptosis and an increased CD44 expression were confirmed by FC, and increased levels of phospho-STAT5 were confirmed by WES Simple in CD34 + cells with MSC-EV. In addition, these cells displayed a higher colony-forming unit granulocyte/macrophage clonogenic potential. Finally, the in vivo bone marrow lodging ability of human CD34 + cells with MSC-EV was significantly increased in the injected femurs. In summary, the incorporation of MSC-EV induces genomic and functional changes in CD34 + cells, increasing their clonogenic capacity and their bone marrow lodging ability. STEM CELLS 2019;37:1357-1368 SIGNIFICANCE STATEMENTIn the current study, the authors validate for the first time that preincubating human CD34 + cells with extracellular vesicles derived from human mesenchymal stromal cells not only modifies the gene expression of the recipient cells (inducing a downregulation of proapoptotic genes and overexpression of genes involved in colony formation and JAK-STAT pathway) but also significantly increases their in vitro clonogenic ability and, most importantly, increases their 4-week bone marrow lodging ability in vivo in a standard xenotransplantation model. This strategy could potentially be exploited to increase the hematopoietic engraftment in the clinical setting.

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Section: Discussionmentioning

confidence: 99%

The Incorporation of Extracellular Vesicles from Mesenchymal Stromal Cells Into CD34+ Cells Increases Their Clonogenic Capacity and Bone Marrow Lodging Ability

et al. 2019

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“…This strategy may be applicable not only to cord blood transplantation but also to bone marrow trans- The inclusion and exclusion criteria of the MSC donors are listed in the study protocol in detail. 35 Patients were excluded if they had history of allogeneic HCT in the 1 year prior to enrollment, exposure to gemtuzumab ozogamicin in the 6 months prior to enrollment, and allergy to the drugs used for transplant preconditioning or GVHD prophylaxis. Exclusion criteria also included positive for HIV antibody, pregnancy or lactation, and uncontrolled psychiatric disorder or infection.…”

Section: Significance Statementmentioning

confidence: 99%

Phase I clinical trial of intra-bone marrow cotransplantation of mesenchymal stem cells in cord blood transplantation

Goto

Murata

Nishida

et al. 2020

Stem Cells Translational Medicine

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Mesenchymal stem cells (MSCs) have immunomodulatory properties and support hematopoiesis in the bone marrow (BM). To develop a new strategy to not only prevent graft-vs-host disease (GVHD) but also to enhance engraftment, a phase I trial of cord blood transplantation (CBT) combined with intra-BM injection of MSCs (MSC-CBT) was designed. Third-party BM-derived MSCs were injected intra-BM on the day of CBT. The conditioning regimen varied according to patient characteristics. GVHD prophylaxis was tacrolimus and methotrexate. The primary endpoint was toxicity related to intra-BM injection of MSCs. Clinical outcomes were compared with those of six controls who received CBT alone. Five adult patients received MSC-CBT, and no adverse events related to intra-BM injection of MSCs were observed. All patients achieved neutrophil, reticulocyte, and platelet recoveries, with median times to recoveries of 21, 35, and 38 days, respectively, comparable with controls. Grade II-IV acute GVHD developed in three controls but not in MSC-CBT patients. No patients developed chronic GVHD in both groups. At 1 year after transplantation, all MSC-CBT patients survived without relapse. This study shows the safety of MSC-CBT, and the findings also suggest that cotransplantation of MSCs may prevent GVHD with no inhibition of engraftment.

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“…The exploitation of this process will be a valuable asset to directed therapy [127]. The capability to express exogenous gene products, genetic stability and allogeneic properties turn MSCs into efficient carriers for antitumor therapy [128]; previously demonstrated not only in tumor models but also in a wide range of other diseases such as graft-versus-host disease, multiple sclerosis, and arthritis [129–131].…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stromal cells induce inhibitory effects on hepatocellular carcinoma through various signaling pathways

Ketabchi

Verdi

et al. 2019

Cancer Cell Int

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Hepatocellular carcinoma (HCC) is the most prevalent type of malignant liver disease worldwide. Molecular changes in HCC collectively contribute to Wnt/β-catenin, as a tumor proliferative signaling pathway, toll-like receptors (TLRs), nuclear factor-kappa B (NF-κB), as well as the c-Jun NH2-terminal kinase (JNK), predominant signaling pathways linked to the release of tumor-promoting cytokines. It should also be noted that the Hippo signaling pathway plays an important role in organ size control, particularly in promoting tumorigenesis and HCC development. Nowadays, mesenchymal stromal cells (MSCs)-based therapies have been the subject of in vitro, in vivo, and clinical studies for liver such as cirrhosis, liver failure, and HCC. At present, despite the importance of basic molecular pathways of malignancies, limited information has been obtained on this background. Therefore, it can be difficult to determine the true concept of interactions between MSCs and tumor cells. What is known, these cells could migrate toward tumor sites so apply effects via paracrine interaction on HCC cells. For example, one of the inhibitory effects of MSCs is the overexpression of dickkopf-related protein 1 (DKK-1) as an important antagonist of the Wnt signaling pathway. A growing body of research challenging the therapeutic roles of MSCs through the secretion of various trophic factors in HCC. This review illustrates the complex behavior of MSCs and precisely how their inhibitory signals interface with HCC tumor cells.

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Phase I study of cord blood transplantation with intrabone marrow injection of mesenchymal stem cells

Cited by 16 publications

References 29 publications

The Incorporation of Extracellular Vesicles from Mesenchymal Stromal Cells Into CD34+ Cells Increases Their Clonogenic Capacity and Bone Marrow Lodging Ability

The Incorporation of Extracellular Vesicles from Mesenchymal Stromal Cells Into CD34+ Cells Increases Their Clonogenic Capacity and Bone Marrow Lodging Ability

Phase I clinical trial of intra-bone marrow cotransplantation of mesenchymal stem cells in cord blood transplantation

Mesenchymal stromal cells induce inhibitory effects on hepatocellular carcinoma through various signaling pathways

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