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Ex vivo expansion

Jennifer L Gori, Jason M Butler, Balvir Kunar, Michael G Poulos, Michael Ginsberg, Daniel J Nolan, Zachary K Norgaard, Jennifer E Adair, Shahin Rafii, Hans-Peter Kiem
: : Successful expansion of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs) would benefit many HSPC transplantation and gene therapy/editing applications. However, current expansion technologies have been limited by a loss of multipotency and self-renewal properties ex vivo. We hypothesized that an ex vivo vascular niche would provide prohematopoietic signals to expand HSPCs while maintaining multipotency and self-renewal. To test this hypothesis, BM autologous CD34(+) cells were expanded in endothelial cell (EC) coculture and transplanted in nonhuman primates...
October 14, 2016: Stem Cells Translational Medicine
Matthew J Scheffel, Gina Scurti, Patricia Simms, Elizabeth Garrett-Mayer, Shikhar Mehrotra, Michael I Nishimura, Christina Voelkel-Johnson
Although adoptive transfer of autologous tumor antigen-specific T-cell immunotherapy can produce remarkable clinical efficacy, most patients do not achieve durable complete responses. We hypothesized that reducing susceptibility of T cells to activation-induced cell death (AICD), which increases during the rapid in vitro expansion of therapeutic T cells before their infusion, might improve the persistence of adoptively transferred cells. Our investigations revealed that repetitive stimulation of the T-cell receptor (TCR) induced AICD, as a result of activating the DNA damage response pathway through ATM-mediated Ser15 phosphorylation of p53...
October 15, 2016: Cancer Research
E Yu, H Ueta, H Kimura, Y Kitazawa, Y Sawanobori, K Matsuno
Graft-versus-host disease (GvHD) following liver transplantation (LT) is a rare but serious complication, with no presently available animal model and no preventive measure. To develop a rat LT-GvHD model, we preconditioned hosts with sublethal irradiation plus reduction of NK cells with anti-CD8α mAb treatment, which invariably resulted in acute LT-GvHD. Compared to those in the peripheral counterpart, graft CD4(+) CD25(-) passenger T cells showed lower alloreactivities in mixed leukocyte culture. Immunohistology revealed that donor CD4(+) T cells migrated and formed clusters with host dendritic cells in secondary lymphoid organs, with early expansion and subsequent accumulation in target organs...
October 12, 2016: American Journal of Transplantation
Piya-On Numpaisal, Benjamin B Rothrauff, Riccardo Gottardi, Chung-Liang Chien, Rocky S Tuan
PURPOSE: Treatment of meniscus tears is a persistent challenge in orthopaedics. Although cell therapies have shown promise in promoting fibrocartilage formation in in vitro and preclinical studies, clinical application has been limited by the paucity of autologous tissue and the need for ex vivo cell expansion. Rapid dissociation of the free edges of the anterior and posterior meniscus with subsequent implantation in a meniscus lesion may overcome these limitations. The purpose of this study was to explore the effect of rapidly dissociated meniscus tissue in enhancing neotissue formation in a radial meniscus tear, as simulated in an in vitro explant model...
October 11, 2016: Connective Tissue Research
Kwan-Long Mung, Yat-Ping Tsui, Evelyn Wing-Yin Tai, Ying-Shing Chan, Daisy Kwok-Yan Shum, Graham Ka-Hon Shea
BACKGROUND: Bone marrow stromal cells (BMSCs) are attractive as a source of neural progenitors for ex vivo generation of neurons and glia. Limited numbers of this subpopulation, however, hinder translation into autologous cell-based therapy. Here, we demonstrate rapid and efficient conditioning with hypoxia to enrich for these neural progenitor cells prior to further expansion in neurosphere culture. METHOD: Adherent cultures of BMSCs (rat/human) were subjected to 1 % oxygen for 24 h and then subcultured as neurospheres with epidermal growth factor (EGF) and basic fibroblast growth factor supplementation...
October 7, 2016: Stem Cell Research & Therapy
Saba Parween, Elena Kostromina, Christoffer Nord, Maria Eriksson, Per Lindström, Ulf Ahlgren
The leptin deficient ob/ob mouse is a widely used model for studies on initial aspects of metabolic disturbances leading to type 2 diabetes, including insulin resistance and obesity. Although it is generally accepted that ob/ob mice display a dramatic increase in β-cell mass to compensate for increased insulin demand, the spatial and quantitative dynamics of β-cell mass distribution in this model has not been assessed by modern optical 3D imaging techniques. We applied optical projection tomography and ultramicroscopy imaging to extract information about individual islet β-cell volumes throughout the volume of ob/ob pancreas between 4 and 52 weeks of age...
October 7, 2016: Scientific Reports
Alba Murgia, Elena Veronesi, Olivia Candini, Anna Caselli, Naomi D'souza, Valeria Rasini, Andrea Giorgini, Fabio Catani, Lorenzo Iughetti, Massimo Dominici, Jorge S Burns
In skeletal regeneration approaches using human bone marrow derived mesenchymal stromal cells (hBM-MSC), functional evaluation before implantation has traditionally used biomarkers identified using fetal bovine serum-based osteogenic induction media and time courses of at least two weeks. However, emerging pre-clinical evidence indicates donor-dependent discrepancies between these ex vivo measurements and the ability to form bone, calling for improved tests. Therefore, we adopted a multiparametric approach aiming to generate an osteogenic potency assay with improved correlation...
2016: PloS One
Mauricio Cortes, Michael J Chen, David L Stachura, Sarah Y Liu, Wanda Kwan, Francis Wright, Linda T Vo, Lindsay N Theodore, Virginie Esain, Isaura M Frost, Thorsten M Schlaeger, Wolfram Goessling, George Q Daley, Trista E North
Vitamin D insufficiency is a worldwide epidemic affecting billions of individuals, including pregnant women and children. Despite its high incidence, the impact of active vitamin D3 (1,25(OH)D3) on embryonic development beyond osteo-regulation remains largely undefined. Here, we demonstrate that 1,25(OH)D3 availability modulates zebrafish hematopoietic stem and progenitor cell (HSPC) production. Loss of Cyp27b1-mediated biosynthesis or vitamin D receptor (VDR) function by gene knockdown resulted in significantly reduced runx1 expression and Flk1(+)cMyb(+) HSPC numbers...
October 4, 2016: Cell Reports
Kelsey A Thomas, Michael C Gibbons, John G Lane, Anshuman Singh, Samuel R Ward, Adam J Engler
Full thickness rotator cuff tendon (RCT) tears have long-term effects on RC muscle atrophy and fatty infiltration, with lasting damage even after surgical tendon repair. Skeletal muscle progenitor cells (SMPs) are critical for muscle repair in response to injury, but the inability of RC muscles to recover from chronic RCT tear indicates possible deficits in repair mechanisms. Here we investigated if muscle injury state was a crucial factor during human SMP expansion and differentiation ex vivo. SMPs were isolated from muscles in patients with no, partial-thickness (PT), or full-thickness (FT) RCT tears...
October 4, 2016: Journal of Orthopaedic Research: Official Publication of the Orthopaedic Research Society
Jacqueline R Benthuysen, Andrea C Carrano, Maike Sander
In the past decade, new approaches have been explored that are aimed at restoring functional β cell mass as a treatment strategy for diabetes. The two most intensely pursued strategies are β cell replacement through conversion of other cell types and β cell regeneration by enhancement of β cell replication. The approach closest to clinical implementation is the replacement of β cells with human pluripotent stem cell-derived (hPSC-derived) cells, which are currently under investigation in a clinical trial to assess their safety in humans...
October 3, 2016: Journal of Clinical Investigation
Min Yu, Sanja Bojic, Gustavo S Figueiredo, Paul Rooney, Julian de Havilland, Anne Dickinson, Francisco C Figueiredo, Majlinda Lako
The cornea is a self-renewing tissue located at the front of the eye. Its transparency is essential for allowing light to focus onto the retina for visual perception. The continuous renewal of corneal epithelium is supported by limbal stem cells (LSCs) which are located in the border region between conjunctiva and cornea known as the limbus. Ex vivo expansion of LSCs has been successfully applied in the last two decades to treat patients with limbal stem cell deficiency (LSCD). Various methods have been used for their expansion, yet the most widely used culture media contains a number of ingredients derived from animal sources which may compromise the safety profile of human LSC transplantation...
September 28, 2016: Experimental Eye Research
Sarvari Velaga, Christina Alter, Ulrike Dringenberg, Christina T Thiesler, Sandra Kuhs, Sven Olek, Sya N Ukena, Anke Franzke
OBJECTIVE: Recent clinical trials have shown the high potential of regulatory T cells (Tregs) in prevention of acute and chronic graft-versus-host disease (GvHD) following hematopoietic stem cell transplantation but immune interventions require high Treg cell numbers. With respect to limited natural occurrence, development and optimization of large-scale expansion protocols of clinical-grade Tregs are essential if considered for therapeutic use. METHODS: We compared different clinical grade large-scale expansion protocols for repetitive transfer of high Treg cell numbers in clinical trials for the prevention of acute and/or chronic GvHD...
September 27, 2016: Experimental Hematology
Doo-Sik Kong, Do-Hyun Nam, Shin-Hyuk Kang, Jae Won Lee, Jong-Hee Chang, Jeong-Hoon Kim, Young-Jin Lim, Young-Cho Koh, Yong-Gu Chung, Jae-Min Kim, Choong-Hyun Kim
PURPOSE: Adoptive cell immunotherapy involves an ex vivo expansion of autologous cytokine-induced killer (CIK) cells before their reinfusion into the host. We evaluated the efficacy and safety of CIK cell immunotherapy with radiotherapy-temozolomide (TMZ) for the treatment of newly diagnosed glioblastomas. EXPERIMENTAL DESIGN: In this multi-center, open-label, phase 3 study, we randomly assigned patients with newly diagnosed glioblastoma to receive CIK cell immunotherapy combined with standard TMZ chemoradiotherapy (CIK immunotherapy group) or standard TMZ chemoradiotherapy alone (control group)...
September 27, 2016: Oncotarget
Heleen H Van Acker, Sébastien Anguille, Yannick Willemen, Johan M Van den Bergh, Zwi N Berneman, Eva Lion, Evelien L Smits, Viggo F Van Tendeloo
BACKGROUND: Adoptive immunotherapy is gaining momentum to fight malignancies, whereby γδ T cells have received recent attention as an alternative cell source as to natural killer cells and αβ T cells. The advent of γδ T cells is largely due to their ability to recognize and target tumor cells using both innate characteristic and T cell receptor (TCR)-mediated mechanisms, their capacity to enhance the generation of antigen-specific T cell responses, and their potential to be used in an autologous or allogeneic setting...
September 29, 2016: Journal of Hematology & Oncology
Juan Ignacio Basile, Denise Kviatcovsky, María Mercedes Romero, Luciana Balboa, Johana Monteserin, Viviana Ritacco, Beatriz Lopez, Carmen Sabio Y García, Ana García, Marisa Vescovo, Pablo González Montaner, Domingo Palmero, María Del Carmen Sasiain, Silvia de la Barrera
We have previously reported that T cells from patients with multidrug-resistant tuberculosis (MDR-TB) express high levels of IL-17 in response to the MDR strain M (Haarlem family) of Mycobacterium tuberculosis (M.tuberculosis). Herein, we explore the pathways involved in the induction of h17 cells in MDR-TB patients and healthy tuberculin reactors (PPD(+) HD) by the M strain and the laboratory strain H37Rv. Our results show that IL-1β and IL-6 are crucial for the H37Rv and M-induced expansion of IL-17(+) IFNγ- and IL-17(+) IFNγ(+) in CD4(+) T cells from MDR-TB and PPD(+) HD...
September 28, 2016: Clinical and Experimental Immunology
Mingyuan Han, Jun Young Hong, Suraj Jaipalli, Charu Rajput, Jing Lei, Joanna L Hinde, Qiang Chen, Natalie M Hershenson, J Kelley Bentley, Marc B Hershenson
Early-life wheezing-associated infections with rhinovirus (RV) have been associated with asthma development in children. We have shown that RV infection of six day-old mice induces mucous metaplasia and airways hyperresponsiveness which is dependent on IL-13, IL-25 and type 2 innate lymphoid cells (ILC2s). Infection of immature mice fails to induce lung IFN-γ expression, in contrast to mature 8 week-old mice with a robust IFN-γ response, consistent with the notion that deficient IFN-γ production in immature mice permits RV-induced type 2 immune responses...
September 28, 2016: American Journal of Respiratory Cell and Molecular Biology
Esther Camp, Peter J Anderson, Andrew C W Zannettino, Stan Gronthos
The TWIST-1 gene encodes a basic helix-loop-helix (bHLH) transcription factor important in mediating skeletal and head mesodermal tissue development. Bone marrow-derived mesenchymal stem/ stromal cells (BMSC), express high levels of TWIST-1, which is down regulated during ex vivo expansion. Cultured BMSC over-expressing TWIST-1 display decreased capacity for osteogenic differentiation and an enhanced capacity to undergo adipogenesis, suggesting that TWIST-1 is a mediator of lineage commitment. However, little is known regarding the mechanism(s) by which TWIST-1 mediates cell fate determination...
September 23, 2016: Bone
Constance Laroche-Lefebvre, Mitra Yousefi, Jean-François Daudelin, Tania Charpentier, Esther Tarrab, Roscoe Klinck, Alain Lamarre, Nathalie Labrecque, Simona Stäger, Pascale Duplay
Diverse signals received by CD8(+) T cells are integrated to achieve the required magnitude of cell expansion and the appropriate balance of effector/memory CD8(+) T cell generation. Notably, the strength and nature of TCR signaling influence the differentiation and functional capacity of effector and memory CD8(+) T cells. Dok-1 and Dok-2, the two members of the Dok family expressed in T cells, negatively regulate TCR signaling in vitro. However, the role of Dok proteins in modulating T cell function in vivo has not yet studied...
September 23, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Sailesh C Harwani, Jason Ratcliff, Fayyaz S Sutterwala, Zuhair K Ballas, David K Meyerholz, Mark W Chapleau, Francois Abboud
RATIONALE: Renal inflammation contributes to the pathophysiology of hypertension. CD161a+ immune cells are dominant in the Spontaneously Hypertensive Rat (SHR) and expand in response to nicotinic cholinergic activation. OBJECTIVE: We aimed to phenotype CD161a+ immune cells in pre-hypertensive SHR following cholinergic activation with nicotine, and determine if these cells are involved in renal inflammation and the development of hypertension. METHODS AND RESULTS: Studies utilized young SHR and Wistar Kyoto (WKY) rats...
September 22, 2016: Circulation Research
M Mohammadi, M R Jaafari, H R Mirzaei, H Mirzaei
Cancer is one of the main problems in public health worldwide. Despite rapid advances in the diagnosis and treatment of cancer, the efficacy of current treatment strategies is still limited. There are promising new results in animal models whereby mesenchymal stem cells (MSCs) can be used as vehicles for targeted therapies. The use of MSCs as therapeutic biological vehicles in cell therapy has several advantages, including immune-silence, tumor tropism, easy and rapid isolation, ex vivo expansion, multilineage differentiation and the capacity to deliver a number of therapeutic agents...
September 2016: Cancer Gene Therapy
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