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Non ablative bone marrow transplantation

Lucinda R Lee, Lauren Peacock, Samantha L Ginn, Laurence C Cantrill, Tegan L Cheng, David G Little, Craig F Munns, Aaron Schindeler
Bone marrow transplantation (BMT) of healthy donor cells has been postulated as a strategy for treating osteogenesis imperfecta (OI) and other bone fragility disorders. The effect of engraftment by tail vein injection and/or marrow ablation by 6 Gy whole body irradiation were tested in Col1a2+/G610C (OI) mice as a model of mild-moderate OI. Dual-emission X-ray absorptiometry, microCT, and 4-point bending were used to measure bone volume (BV), bone mineral density (BMD), and biomechanical strength. BV, BMD, and mechanical strength were reduced in OI mice compared to wild type (WT) controls...
December 8, 2018: Calcified Tissue International
Divya Devadasan, Chiao-Wang Sun, Erik R Westin, Li-Chen Wu, Kevin M Pawlik, Tim M Townes, Frederick D Goldman
Allogeneic hematopoietic stem cell transplantation (HSCT) can be curative for patients with sickle cell disease (SCD). However, morbidity associated with myeloablative conditioning and graft-versus-host disease has limited its utility. To this end, autologous HSCT for SCD using lentiviral gene-modified bone marrow (BM) or peripheral blood stem cells has been undertaken, although toxicities of fully ablative conditioning with busulfan and incomplete engraftment have been encountered. Treosulfan, a busulfan analog with a low extramedullary toxicity profile, has been used successfully as part of a myeloablative conditioning regimen in the allogeneic setting in SCD...
August 2018: Biology of Blood and Marrow Transplantation
Fu-Han Gong, Wen-Lin Cheng, Haiping Wang, Maomao Gao, Juan-Juan Qin, Yan Zhang, Xia Li, Xueyong Zhu, Hao Xia, Zhi-Gang She
Atherosclerosis is considered to be a chronic inflammatory disease that can lead to severe clinically important cardiovascular events. miR-150 is a small noncoding RNA that significantly enhances inflammatory responses by upregulating endothelial cell proliferation and migration, as well as intravascular environmental homeostasis. However, the exact role of miR-150 in atherosclerosis remains unknown. Here, we investigated the effect of miR-150 deficiency on atherosclerosis development. Using double-knockout (miR-150-/- and ApoE-/- ) mice, we measured atherosclerotic lesion size and stability...
April 2018: Journal of Lipid Research
Teresa Monkkonen, John D Landua, Adriana P Visbal, Michael T Lewis
Patched 1 ( Ptch1 ) has epithelial, stromal and systemic roles in murine mammary gland organogenesis, yet specific functions remain undefined. Cre -recombinase-mediated Ptch1 ablation in mammary epithelium increased proliferation and branching, but did not phenocopy transgenic expression of activated smoothened ( SmoM2 ). The epithelium showed no evidence of canonical hedgehog signaling, and hyperproliferation was not blocked by smoothened (SMO) inhibition, suggesting a non-canonical function of PTCH1. Consistent with this possibility, nuclear localization of cyclin B1 was increased...
April 1, 2017: Development
Jessica C Petrov, Anastasia Nijnik
Myb-Like SWIRM and MPN domains 1 (MYSM1) is a chromatin-binding protein, essential for hematopoietic stem cell (HSC) maintenance and differentiation in humans and mouse models. HSCs in mammalian bone marrow exist in close interactions with many non-hematopoietic cell types in their microenvironment, collectively known as the bone marrow niche. Although cell-intrinsic activities of MYSM1 within the hematopoietic cells are known to play an important role in hematopoietic homeostasis, Mysm1 expression is also widely observed in non-hematopoietic cells, and MYSM1 is implicated as an important regulator of mesenchymal stem cell differentiation, osteoblast function, and adipogenesis within the bone marrow...
March 2017: Experimental Hematology
Tom Verbiest, Rosemary Finnon, Natalie Brown, Paul Finnon, Simon Bouffler, Christophe Badie
Scid hematopoietic stem cells (HSCs) have an intrinsic defect in their maintenance within the bone marrow (BM) niche which facilitates HSC transplantation without the absolute requirement of prior conditioning. Nevertheless, NOD scid mice have a significantly altered life span due to early development of thymic lymphomas, which compromises the ability to study the long-term fate of exogenous HSCs and their progeny. Here, we present data on the transplantation of HSCs into NOD scid gamma (NSG) mice to achieve long-term engraftment without prior conditioning...
November 7, 2016: International Journal of Molecular Sciences
Ting Yang, Qiaoxian Lin, Jinhua Ren, Ping Chen, Xiaohong Yuan, Xiaofeng Luo, Tingbo Liu, Jing Zheng, Zhihong Zheng, Xiaoyun Zheng, Xinji Chen, Langhui Zhang, Hao Zheng, Zaisheng Chen, Xueling Hua, Shaohua Le, Jian Li, Zhizhe Chen, Jianda Hu
Haplo-HSCT has been used when HLA-matched siblings are not available. Conditioning regimens aim to reduce tumor burden prior to HSCT and provide sufficient immunoablation. We report the outcome of haplo-HSCT in 63 consecutive patients from 2/2013 to 12/2015 (19 females/44 males) with high-risk or relapsed/refractory hematological malignancies (n=29-AML; 8-sAML; 19-ALL; 5-advanced-MDS; 2-CML-BC). Median age was 20 years (range: 1.1-49). Twenty-one patients achieved remission prior to transplant, while 42 did not...
November 29, 2016: Oncotarget
Hideto Koso, Asano Tsuhako, Chen-Yi Lai, Yukihiro Baba, Makoto Otsu, Kazuko Ueno, Masao Nagasaki, Yutaka Suzuki, Sumiko Watanabe
Neurodegeneration has been shown to induce microglial activation and the infiltration of monocyte-derived macrophages into the CNS, resulting in the coexistence of these two populations within the same lesion, though their distinct features remain elusive. To investigate the impact of rod photoreceptor degeneration on microglial activation, we generated a toxin-mediated genetic model of rod degeneration. Rod injury induced microglial proliferation and migration toward the photoreceptors. Bone marrow transplantation revealed the invasion of monocyte-derived macrophages into the retina, with microglia and the infiltrating macrophages showing distinct distribution patterns in the retina...
November 2016: Glia
Umang G Thakkar, Hargovind L Trivedi, Aruna V Vanikar, Shruti D Dave
BACKGROUND AIMS: Stem cell therapy (SCT) is now the up-coming therapeutic modality for treatment of type 1 diabetes mellitus (T1DM). METHODS: Our study was a prospective, open-labeled, two-armed trial for 10 T1DM patients in each arm of allogenic and autologous adipose-derived insulin-secreting mesenchymal stromal cells (IS-AD-MSC)+bone marrow-derived hematopoietic stem cell (BM-HSC) infusion. Group 1 received autologous SCT: nine male patients and one female patient; mean age, 20...
July 2015: Cytotherapy
Marie-Christine Vantyghem, Jérôme Cornillon, Christine Decanter, Frédérique Defrance, Wassila Karrouz, Clara Leroy, Kristell Le Mapihan, Marie-Anne Couturier, Eva De Berranger, Eric Hermet, Natacha Maillard, Ambroise Marcais, Sylvie Francois, Reza Tabrizi, Ibrahim Yakoub-Agha
Allogeneic hematopoietic stem cell transplantation is mainly indicated in bone marrow dysfunction related to blood diseases, but also in some rare diseases (adrenoleucodystrophy, mitochondrial neurogastrointestinal encephalomyopathy or MNGIE...). After decades, this treatment has proven to be efficient at the cost of numerous early and delayed side effects such as infection, graft-versus-host disease, cardiovascular complications and secondary malignancies. These complications are mainly related to the conditioning, which requires a powerful chemotherapy associated to total body irradiation (myelo-ablation) or immunosuppression (non myelo-ablation)...
October 29, 2014: Orphanet Journal of Rare Diseases
Ayako Nakamura-Ishizu, Keiyo Takubo, Masato Fujioka, Toshio Suda
Tissue homeostasis demands regulatory feedback, suggesting that hematopoietic stem cell (HSC) activity is controlled in part by HSC progeny. Yet, cell extrinsic HSC regulation has been well characterized only in niche cells of non-hematopoietic origin. Here we identify feedback regulation of HSCs by megakaryocytes (Mks), which are mature hematopoietic cells, through production of thrombopoietin (Thpo), a cytokine pertinent for HSC maintenance. Induced ablation of Mk cell population in mice perturbed quiescent HSCs in bone marrow (BM)...
November 14, 2014: Biochemical and Biophysical Research Communications
Karen F Buckland, H Bobby Gaspar
The range of possible gene and cell therapy applications is expanding at an extremely rapid rate and advanced therapy medicinal products (ATMPs) are currently the hottest topic in novel medicines, particularly for inherited diseases. Paediatric patients stand to gain enormously from these novel therapies as it now seems plausible to develop a gene or cell therapy for a vast number of inherited diseases. There are a wide variety of potential gene and cell therapies in various stages of development. Patients who received first gene therapy treatments for primary immune deficiencies (PIDs) are reaching 10 and 15 years post-treatment, with robust and sustained immune recovery...
June 2014: Advanced Drug Delivery Reviews
Sarita Olteanu, Michal Kandel-Kfir, Aviv Shaish, Tal Almog, Shay Shemesh, Iris Barshack, Ron N Apte, Dror Harats, Yehuda Kamari
BACKGROUND: The role of Kupffer cell interleukin (IL)-1 in non-alcoholic steatohepatitis development remains unclear. AIMS: To evaluate the role of Kupffer cell IL-1α, IL-1β or IL-1 receptor type-1 (IL-1R1) in steatohepatitis. METHODS: C57BL/6 mice were irradiated and transplanted with bone marrow-derived cells from WT, IL-1α-/-, IL-1β-/- or IL-1R1-/- mice combined with Kupffer cell ablation with Gadolinium Chloride, and fed atherogenic diet...
May 2014: Digestive and Liver Disease
C L Teigland, R E Parrott, R H Buckley
SCID is a fatal syndrome caused by mutations in at least 13 different genes. It is characterized by the absence of T cells. Immune reconstitution can be achieved through nonablative related donor BMT. However, the first transplant may not provide sufficient immunity. In these cases, booster transplants may be helpful. A prospective/retrospective study was conducted of 49 SCID patients (28.7% of 171 SCIDs transplanted over 30 years) who had received booster transplants to define the long-term outcome, factors contributing to a need for a booster and factors that predicted success...
August 2013: Bone Marrow Transplantation
Maria Elena De Obaldia, J Jeremiah Bell, Avinash Bhandoola
The mouse thymus supports T-cell development, but also contains non-T-cell lineages such as dendritic cells, macrophages, and granulocytes that are necessary for T-cell repertoire selection and apoptotic thymocyte clearance. Early thymic progenitors (ETPs) are not committed to the T-cell lineage, as demonstrated by both in vitro and in vivo assays. Whether ETPs realize non-T-cell lineage potentials in vivo is not well understood and indeed is controversial. In the present study, we investigated whether ETPs are the major precursors of any non-T-lineage cells in the thymus...
January 3, 2013: Blood
Rebecca H Buckley, Chan M Win, Barry K Moser, Roberta E Parrott, Elisa Sajaroff, Marcella Sarzotti-Kelsoe
PURPOSE: Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B and sometimes NK cell function. Non-ablative HLA-identical or rigorously T cell-depleted haploidentical parental bone marrow transplantation (BMT) results in thymus-dependent genetically donor T cell development in the recipients, leading to a high rate of long-term survival. However, the development of B cell function has been more problematic. We report here results of analyses of B cell function in 125 SCID recipients prior to and long-term after non-ablative BMT, according to their molecular type...
January 2013: Journal of Clinical Immunology
G Sergiacomi, E Gaspari, A Taglieri, A Meschini, V Gisone, L Cudillo, W Arcese, G Simonetti
PURPOSE: This study evaluated the usefulness of 3-Tesla magnetic resonance (MR) spectroscopy in patients with non-Hodgkin's lymphoma (NHL) undergoing bone marrow transplantation (BMT). MATERIALS AND METHODS: Twelve NHL patients who were candidates for BMT underwent three MR examinations of the lumbosacral spine: before ablative therapy for BMT, 15±4 days and 54±24 days after BMT. The MR study was supplemented by spectroscopic analysis. The lipid content was calculated and expressed as a percentage of lipid signal intensity relative to total signal intensity [fat fraction (FF)]...
February 2013: La Radiologia Medica
Niki Tsakiri, Dimitrios Papadopoulos, Maria C Denis, Dimos-Dimitrios Mitsikostas, George Kollias
The TNF/TNFR system exerts multiple proinflammatory and immunosuppressive functions in the pathogenesis of chronic inflammation and autoimmunity. In EAE, the experimental model of Multiple Sclerosis (MS), genetic ablation of TNFR2, results in exacerbated immune reactivity and chronic disease course. The underlying mechanism driving this immunosuppressive function of TNFR2 remains unclear. We show here that chronic exacerbated EAE in TNFR2 KO mice is associated with increased Th17-cell responses and reduced numbers of Foxp3(+) Treg cells both in the spinal cord and peripheral lymphoid organs...
February 2012: European Journal of Immunology
Joyce T O'Connell, Hikaru Sugimoto, Vesselina G Cooke, Brian A MacDonald, Ankit I Mehta, Valerie S LeBleu, Rajan Dewar, Rafael M Rocha, Ricardo R Brentani, Murray B Resnick, Eric G Neilson, Michael Zeisberg, Raghu Kalluri
Increased numbers of S100A4(+) cells are associated with poor prognosis in patients who have cancer. Although the metastatic capabilities of S100A4(+) cancer cells have been examined, the functional role of S100A4(+) stromal cells in metastasis is largely unknown. To study the contribution of S100A4(+) stromal cells in metastasis, we used transgenic mice that express viral thymidine kinase under control of the S100A4 promoter to specifically ablate S100A4(+) stromal cells. Depletion of S100A4(+) stromal cells significantly reduced metastatic colonization without affecting primary tumor growth...
September 20, 2011: Proceedings of the National Academy of Sciences of the United States of America
Steven Maltby, Spencer Freeman, Matthew J Gold, Jennifer H E Baker, Andrew I Minchinton, Michael R Gold, Calvin D Roskelley, Kelly M McNagny
Tumor growth and metastasis are determined by the complex interplay of factors, including those intrinsic to tumor cells and extrinsic factors associated with the tumor microenvironment. Our previous work demonstrated key roles for CD34 in the maintenance of vascular integrity and eosinophil and mast cell homing. Since both of these functions affect tumor development, we characterized the effect of CD34 ablation on tumor growth using the B16F1 melanoma model. Intriguingly, we found that CD34 plays a biphasic role in tumor progression...
2011: PloS One
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