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https://www.readbyqxmd.com/read/28541275/engineering-the-haemogenic-niche-mitigates-endogenous-inhibitory-signals-and-controls-pluripotent-stem-cell-derived-blood-emergence
#1
Nafees Rahman, Patrick M Brauer, Lilian Ho, Tatiana Usenko, Mukul Tewary, Juan Carlos Zúñiga-Pflücker, Peter W Zandstra
Efforts to recapitulate haematopoiesis, a process guided by spatial and temporal inductive signals, to generate haematopoietic progenitors from human pluripotent stem cells (hPSCs) have focused primarily on exogenous signalling pathway activation or inhibition. Here we show haemogenic niches can be engineered using microfabrication strategies by micropatterning hPSC-derived haemogenic endothelial (HE) cells into spatially-organized, size-controlled colonies. CD34+VECAD+ HE cells were generated with multi-lineage potential in serum-free conditions and cultured as size-specific haemogenic niches that displayed enhanced blood cell induction over non-micropatterned cultures...
May 25, 2017: Nature Communications
https://www.readbyqxmd.com/read/28515359/t-cell-progenitor-therapy-facilitated-thymopoiesis-depends-upon-thymic-input-and-continued-thymic-microenvironment-interaction
#2
Michelle J Smith, Dawn K Reichenbach, Sarah L Parker, Megan J Riddle, Jason Mitchell, Kevin C Osum, Mahmood Mohtashami, Heather E Stefanski, Brian T Fife, Avinash Bhandoola, Kristin A Hogquist, Georg A Holländer, Juan Carlos Zúñiga-Pflücker, Jakub Tolar, Bruce R Blazar
Infusion of in vitro-derived T cell progenitor (proT) therapy with hematopoietic stem cell transplant aids the recovery of the thymus damaged by total body irradiation. To understand the interaction between proTs and the thymic microenvironment, WT mice were lethally irradiated and given T cell-deficient (Rag1-/-) marrow with WT in vitro-generated proTs, limiting mature T cell development to infused proTs. ProTs within the host thymus led to a significant increase in thymic epithelial cells (TECs) by day 21 after transplant, increasing actively cycling TECs...
May 18, 2017: JCI Insight
https://www.readbyqxmd.com/read/28394335/progenitor-t-cell-differentiation-from-hematopoietic-stem-cells-using-delta-like-4-and-vcam-1
#3
Shreya Shukla, Matthew A Langley, Jastaranpreet Singh, John M Edgar, Mahmood Mohtashami, Juan Carlos Zúñiga-Pflücker, Peter W Zandstra
The molecular and cellular signals that guide T-cell development from hematopoietic stem and progenitor cells (HSPCs) remain poorly understood. The thymic microenvironment integrates multiple niche molecules to potentiate T-cell development in vivo. Recapitulating these signals in vitro in a stromal cell-free system has been challenging and limits T-cell generation technologies. Here, we describe a fully defined engineered in vitro niche capable of guiding T-lineage development from HSPCs. Synergistic interactions between Notch ligand Delta-like 4 and vascular cell adhesion molecule 1 (VCAM-1) were leveraged to enhance Notch signaling and progenitor T-cell differentiation rates...
May 2017: Nature Methods
https://www.readbyqxmd.com/read/28148688/extl3-mutations-cause-skeletal-dysplasia-immune-deficiency-and-developmental-delay
#4
Stefano Volpi, Yasuhiro Yamazaki, Patrick M Brauer, Ellen van Rooijen, Atsuko Hayashida, Anne Slavotinek, Hye Sun Kuehn, Maja Di Rocco, Carlo Rivolta, Ileana Bortolomai, Likun Du, Kerstin Felgentreff, Lisa Ott de Bruin, Kazutaka Hayashida, George Freedman, Genni Enza Marcovecchio, Kelly Capuder, Prisni Rath, Nicole Luche, Elliott J Hagedorn, Antonella Buoncompagni, Beryl Royer-Bertrand, Silvia Giliani, Pietro Luigi Poliani, Luisa Imberti, Kerry Dobbs, Fabienne E Poulain, Alberto Martini, John Manis, Robert J Linhardt, Marita Bosticardo, Sergio Damian Rosenzweig, Hane Lee, Jennifer M Puck, Juan Carlos Zúñiga-Pflücker, Leonard Zon, Pyong Woo Park, Andrea Superti-Furga, Luigi D Notarangelo
We studied three patients with severe skeletal dysplasia, T cell immunodeficiency, and developmental delay. Whole-exome sequencing revealed homozygous missense mutations affecting exostosin-like 3 (EXTL3), a glycosyltransferase involved in heparan sulfate (HS) biosynthesis. Patient-derived fibroblasts showed abnormal HS composition and altered fibroblast growth factor 2 signaling, which was rescued by overexpression of wild-type EXTL3 cDNA. Interleukin-2-mediated STAT5 phosphorylation in patients' lymphocytes was markedly reduced...
March 6, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27789110/t-cell-genesis-in-vitro-veritas-est
#5
REVIEW
Patrick M Brauer, Jastaranpreet Singh, Sintia Xhiku, Juan Carlos Zúñiga-Pflücker
T cells, as orchestrators of the adaptive immune response, serve important physiological and potentially therapeutic roles, for example in cancer immunotherapy. T cells are readily isolated from patients; however, the yield of antigen-specific T cells is limited, thus making their clinical use challenging. Therefore, the generation of T lymphocytes from hematopoietic stem/progenitor cells (HSPCs) and human pluripotent stem cells (PSCs) in vitro provides an attractive method for the large-scale production and genetic manipulation of T cells...
December 2016: Trends in Immunology
https://www.readbyqxmd.com/read/27301863/modeling-altered-t-cell-development-with-induced-pluripotent-stem-cells-from-patients-with-rag1-dependent-immune-deficiencies
#6
Patrick M Brauer, Itai M Pessach, Erik Clarke, Jared H Rowe, Lisa Ott de Bruin, Yu Nee Lee, Carmen Dominguez-Brauer, Anne M Comeau, Geneve Awong, Kerstin Felgentreff, Yuhang H Zhang, Andrea Bredemeyer, Waleed Al-Herz, Likun Du, Francesca Ververs, Marion Kennedy, Silvia Giliani, Gordon Keller, Barry P Sleckman, David G Schatz, Frederic D Bushman, Luigi D Notarangelo, Juan Carlos Zúñiga-Pflücker
Primary immunodeficiency diseases comprise a group of heterogeneous genetic defects that affect immune system development and/or function. Here we use in vitro differentiation of human induced pluripotent stem cells (iPSCs) generated from patients with different recombination-activating gene 1 (RAG1) mutations to assess T-cell development and T-cell receptor (TCR) V(D)J recombination. RAG1-mutants from severe combined immunodeficient (SCID) patient cells showed a failure to sustain progression beyond the CD3(--)CD4(-)CD8(-)CD7(+)CD5(+)CD38(-)CD31(-/lo)CD45RA(+) stage of T-cell development to reach the CD3(-/+)CD4(+)CD8(+)CD7(+)CD5(+)CD38(+)CD31(+)CD45RA(-) stage...
August 11, 2016: Blood
https://www.readbyqxmd.com/read/27297795/high-content-screening-identifies-kinase-inhibitors-that-overcome-venetoclax-resistance-in-activated-cll-cells
#7
Sina Oppermann, Jarkko Ylanko, Yonghong Shi, Santosh Hariharan, Christopher C Oakes, Patrick M Brauer, Juan C Zúñiga-Pflücker, Brian Leber, David E Spaner, David W Andrews
Novel agents such as the Bcl-2 inhibitor venetoclax (ABT-199) are changing treatment paradigms for chronic lymphocytic leukemia (CLL) but important problems remain. Although some patients exhibit deep and durable responses to venetoclax as a single agent, other patients harbor subpopulations of resistant leukemia cells that mediate disease recurrence. One hypothesis for the origin of resistance to venetoclax is by kinase-mediated survival signals encountered in proliferation centers that may be unique for individual patients...
August 18, 2016: Blood
https://www.readbyqxmd.com/read/26294407/induction-of-t-cell-development-in-vitro-by-delta-like-dll-expressing-stromal-cells
#8
Mahmood Mohtashami, Payam Zarin, Juan Carlos Zúñiga-Pflücker
Recreating the thymic microenvironment in vitro poses a great challenge to immunologists. Until recently, the only approach was to utilize the thymic tissue in its three-dimensional form and to transfer the hematopoietic progenitors into this tissue to generate de novo T cells. With the advent of OP9-DL cells (bone marrow-derived cells that are transduced to express Notch ligand, Delta-like), hematopoietic stem cells (HSC) could be induced to differentiate into T cells in culture for the first time outside of the thymic tissue on a monolayer...
2016: Methods in Molecular Biology
https://www.readbyqxmd.com/read/26227158/in-vitro-t-cell-generation-from-adult-embryonic-and-induced-pluripotent-stem-cells-many-roads-to-one-destination
#9
REVIEW
Michelle J Smith, Beau R Webber, Mahmood Mohtashami, Heather E Stefanski, Juan Carlos Zúñiga-Pflücker, Bruce R Blazar
T lymphocytes are critical mediators of the adaptive immune system and have the capacity to serve as therapeutic agents in the areas of transplant and cancer immunotherapy. While T cells can be isolated and expanded from patients, T cells derived in vitro from both hematopoietic stem/progenitor cells (HSPCs) and human pluripotent stem cells (hPSCs) offer great potential advantages in generating a self-renewing source of T cells that can be readily genetically modified. T-cell differentiation in vivo is a complex process requiring tightly regulated signals; providing the correct signals in vitro to induce T-cell lineage commitment followed by their development into mature, functional, single positive T cells, is similarly complex...
November 2015: Stem Cells
https://www.readbyqxmd.com/read/25941319/t-cell-development-runs-marrow-deep
#10
COMMENT
Juan Carlos Zúñiga-Pflücker
No abstract text is available yet for this article.
May 4, 2015: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/25889009/hematopoiesis-from-start-to-immune-reconstitution-potential
#11
REVIEW
Haydn C-Y Liang, Juan Carlos Zúñiga-Pflücker
The study of hematopoiesis has been a focus for developmental biologists for over 100 years. What started as a series of microscopic observations in different animal model systems has since evolved into studies of gene expression and regulation, and subsequent protein-protein interactions, cell surface protein expression profiling, and functional mapping of cell fates. In this review, we will discuss the milestone discoveries that have been achieved in the field of hematopoietic development, as well as the techniques that have been employed...
April 11, 2015: Stem Cell Research & Therapy
https://www.readbyqxmd.com/read/25866401/gamma-delta-t-cell-differentiation-and-effector-function-programming-tcr-signal-strength-when-and-how-much
#12
REVIEW
Payam Zarin, Edward L Y Chen, Tracy S H In, Michele K Anderson, Juan Carlos Zúñiga-Pflücker
γδ T-cells boast an impressive functional repertoire that can paint them as either champions or villains depending on the environmental and immunological cues. Understanding the function of the various effector γδ subsets necessitates tracing the developmental program of these subsets, including the point of lineage bifurcation from αβ T-cells. Here, we review the importance of signals from the T-cell receptor (TCR) in determining αβ versus γδ lineage fate, and further discuss how the molecular components of this pathway may influence the developmental programming of γδ T-cells functional subsets...
July 2015: Cellular Immunology
https://www.readbyqxmd.com/read/25526308/noncanonical-mode-of-erk-action-controls-alternative-%C3%AE-%C3%AE-and-%C3%AE-%C3%AE-t-cell-lineage-fates
#13
Sang-Yun Lee, Francis Coffey, Shawn P Fahl, Suraj Peri, Michele Rhodes, Kathy Q Cai, Michael Carleton, Stephen M Hedrick, Hans Joerg Fehling, Juan Carlos Zúñiga-Pflücker, Dietmar J Kappes, David L Wiest
Gradations in extracellular regulated kinase (ERK) signaling have been implicated in essentially every developmental checkpoint or differentiation process encountered by lymphocytes. Yet, despite intensive effort, the molecular basis by which differences in ERK activation specify alternative cell fates remains poorly understood. We report here that differential ERK signaling controls lymphoid-fate specification through an alternative mode of action. While ERK phosphorylates most substrates, such as RSK, by targeting them through its D-domain, this well-studied mode of ERK action was dispensable for development of γδ T cells...
December 18, 2014: Immunity
https://www.readbyqxmd.com/read/25517607/dedicated-mtec-progenitors-stay-true-even-into-adulthood
#14
COMMENT
Korosh Kianizad, Juan Carlos Zúñiga-Pflücker
Knowledge about the cells giving rise to and maintaining the thymic structure remains limited. In this issue of Immunity, Sekai et al. (2014) identify a postnatal self-renewing unipotential progenitor population capable of generating thymic medullary cells and lay the foundation for research into thymic regeneration.
November 20, 2014: Immunity
https://www.readbyqxmd.com/read/25357997/a-monoclonal-antibody-against-the-extracellular-domain-of-mouse-and-human-epithelial-v-like-antigen-1-reveals-a-restricted-expression-pattern-among-cd4-cd8-thymocytes
#15
Nahir Garabatos, Jesus Blanco, Cesar Fandos, Elena Lopez, Pere Santamaria, Andrea Ruiz, Maria Laura Perez-Vidakovics, Patricia Benveniste, Oleksandr Galkin, Juan Carlos Zuñiga-Pflucker, Pau Serra
Expression of transcripts for the homotypic adhesion protein epithelial V-like antigen 1 (EVA1), also known as myelin protein zero like-2 (Mpzl2), is known to be present in thymic stromal cells. However, protein expression within different thymic subsets, stromal and/or lymphoid, has not been characterized due a lack of specific reagents. To address this, we generated a hybridoma (G9P3-1) secreting a monoclonal antibody (G9P3-1Mab), reactive against both human and mouse EVA1. The G9P3-1Mab was generated by immunizing Mpzl2-deficient gene-targeted mice with the extracellular domain of EVA1, followed by a conventional hybridoma fusion protocol, illustrating the feasibility of using gene-targeted mice to generate monoclonal antibodies with multiple species cross-reactivity...
October 2014: Monoclonal Antibodies in Immunodiagnosis and Immunotherapy
https://www.readbyqxmd.com/read/25349888/derivation-of-t-cells-in-vitro-from-mouse-embryonic-stem-cells
#16
Martina Kučerová-Levisohn, Jordana Lovett, Armin Lahiji, Roxanne Holmes, Juan Carlos Zúñiga-Pflücker, Benjamin D Ortiz
The OP9/OP9-DL1 co-culture system has become a well-established method for deriving differentiated blood cell types from embryonic and hematopoietic progenitors of both mouse and human origin. It is now used to address a growing variety of complex genetic, cellular and molecular questions related to hematopoiesis, and is at the cutting edge of efforts to translate these basic findings to therapeutic applications. The procedures are straightforward and routinely yield robust results. However, achieving successful hematopoietic differentiation in vitro requires special attention to the details of reagent and cell culture maintenance...
2014: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/25138665/an-in-vitro-model-of-innate-lymphoid-cell-function-and-differentiation
#17
D S J Allan, C L Kirkham, O A Aguilar, L C Qu, P Chen, J H Fine, P Serra, G Awong, J L Gommerman, J C Zúñiga-Pflücker, J R Carlyle
Innate lymphoid cells (ILC) are RAG-independent lymphocytes with important roles in innate immunity, and include group-1 (natural killer (NK) cell, ILC1), group-2 (ILC2), and group-3 (lymphoid tissue inducer (LTi), NCR(+) ILC3) subsets. Group-3 ILC express Rorγt, produce interleukin (IL)-22, and are critically important in the normal function of mucosal tissues. Here, we describe a novel model cell line for the study of ILC function and differentiation. The parental MNK cell line, derived from NKR-P1B(+) fetal thymocytes, shows a capacity to differentiate in γc cytokines...
March 2015: Mucosal Immunology
https://www.readbyqxmd.com/read/24936476/foxn1-gfp-w-reporter-hescs-enable-identification-of-integrin-%C3%AE-4-hla-dr-and-epcam-as-markers-of-human-psc-derived-foxn1-thymic-epithelial-progenitors
#18
Chew-Li Soh, Antonietta Giudice, Robert A Jenny, David A Elliott, Tanya Hatzistavrou, Suzanne J Micallef, Korosh Kianizad, Natalie Seach, Juan Carlos Zúñiga-Pflücker, Ann P Chidgey, Alan Trounson, Susan K Nilsson, David N Haylock, Richard L Boyd, Andrew G Elefanty, Edouard G Stanley
Thymic epithelial cells (TECs) play a critical role in T cell maturation and tolerance induction. The generation of TECs from in vitro differentiation of human pluripotent stem cells (PSCs) provides a platform on which to study the mechanisms of this interaction and has implications for immune reconstitution. To facilitate analysis of PSC-derived TECs, we generated hESC reporter lines in which sequences encoding GFP were targeted to FOXN1, a gene required for TEC development. Using this FOXN1 (GFP/w) line as a readout, we developed a reproducible protocol for generating FOXN1-GFP(+) thymic endoderm cells...
June 3, 2014: Stem Cell Reports
https://www.readbyqxmd.com/read/24799532/new-role-identified-for-lrr-containing-proteins-in-t-cell-development
#19
COMMENT
Juan-Carlos Zúñiga-Pflücker
No abstract text is available yet for this article.
May 5, 2014: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/24748636/an-overview-of-the-intrathymic-intricacies-of-t-cell-development
#20
REVIEW
Divya K Shah, Juan Carlos Zúñiga-Pflücker
The generation of a functional and diverse repertoire of T cells occurs in the thymus from precursors arriving from the bone marrow. In this article, we introduce the various stages of mouse thymocyte development and highlight recent work using various in vivo, and, where appropriate, in vitro models of T cell development that led to discoveries in the regulation afforded by transcription factors and receptor-ligand signaling pathways in specifying, maintaining, and promoting the T cell lineage and the production of T cells...
May 1, 2014: Journal of Immunology: Official Journal of the American Association of Immunologists
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