P W Kincade

Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, United States

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Publications (277)2042.96 Total impact

  • No preview · Article · Sep 2015 · Experimental Hematology
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    ABSTRACT: Mammals have evolved to protect their offspring during early fetal development. Elaborated mechanisms induce tolerance in the maternal immune system for the fetus. Female hormones, mainly estrogen, play a role in suppressing maternal lymphopoiesis. However, the molecular mechanisms involved in the maternal immune tolerance are largely unknown. Here, we show that estrogen-induced soluble Frizzled-related proteins (sFRPs), and particularly sFRP5, suppress B-lymphopoiesis in vivo in transgenic mice. Mice overexpressing sFRP5 had fewer B-lymphocytes in the peripheral blood and spleen. High levels of sFRP5 inhibited early B-cell differentiation in the bone marrow (BM), resulting in the accumulation of cells with a common lymphoid progenitor (CLP) phenotype. Conversely, sFRP5 deficiency reduced the number of hematopoietic stem cells (HSCs) and primitive lymphoid progenitors in the BM, particularly when estrogen was administered. Furthermore, a significant reduction in CLPs and B-lineage-committed progenitors was observed in the BM of sfrp5-null pregnant females. We concluded that, although high sFRP5 expression inhibits B-lymphopoiesis in vivo, physiologically, it contributes to the preservation of very primitive lymphopoietic progenitors, including HSCs, under high estrogen levels. Thus, sFRP5 regulates early lympho-hematopoiesis in the maternal BM, but the maternal-fetal immune tolerance still involves other molecular mechanisms which remain to be uncovered. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Full-text · Article · Feb 2015 · European Journal of Immunology
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    ABSTRACT: Remarkable progress has been made in characterizing factors controlling lineage fate decisions of primitive progenitors that initiate the lymphoid program in bone marrow. However, the understanding of neonatal/adult differences in environmental signals that influence differentiation pathway stability is still incomplete. Our recent findings suggest that Toll-like receptors (TLR) provide a mechanism for producing cells of the innate immune system from early stages of lymphoid development in mice. We now show that both, human early multi-lymphoid progenitors (MLP) and more differentiated lymphoid progenitors from normal adult bone marrow express TLR9. Furthermore, they respond to its ligation by up-regulating the expression of IL15Rβ (CD122) and accelerating the production of functional natural killer (NK)-like cells. Proliferation of the presumed equivalent progenitor cells from umbilical cord blood was stimulated by CpG-ODN or HSV, but the already robust NK cell formation was unchanged. This new information adds to other known differences between neonatal and adult lymphoid progenitors and suggests only the latter replenish innate NK-like cells in response to TLR agonists.
    No preview · Article · Apr 2014 · Experimental hematology
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    Robert S Welner · Paul W Kincade
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    ABSTRACT: In this issue of Cell Stem Cell, Zhao et al. (2014) and Schürch et al. (2014) describe two new stem cell mechanisms underlying protective responses to infection. In response to inflammatory signals, HSPCs and MSCs produce cytokines that stimulate HSC mobilization and differentiation toward innate immune cells at the expense of adaptive immune lineages.
    Preview · Article · Apr 2014 · Cell stem cell
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    ABSTRACT: Although extremely rare, hematopoietic stem cells (HSCs) are divisible into subsets that differ with respect to differentiation potential and cell surface marker expression. For example, we recently found that CD86- CD150+ CD48- HSCs have limited potential for lymphocyte production. This could be an important new tool for studying hematological abnormalities. Here, we analyzed HSC subsets with a series of stem cell markers in JAK2V617F transgenic (Tg) mice, where the mutation is sufficient to cause myeloproliferative neoplasia with lymphocyte deficiency. Total numbers of HSC were elevated 3 to 20 fold in bone marrow of JAK2V617F mice. Careful analysis suggested the accumulation involved multiple HSC subsets, but particularly those characterized as CD150HI CD86- CD18L°CD41+ and excluding Hoechst dye. Real-Time PCR analysis of their HSC revealed that the erythropoiesis associated gene transcripts Gata1, Klf1 and Epor were particularly high. Flow cytometry analyses based on two differentiation schemes for multipotent progenitors (MPP) also suggested alteration by JAK2 signals. The low CD86 on HSC and multipotent progenitors paralleled the large reductions we found in lymphoid progenitors, but the few that were produced functioned normally when sorted and placed in culture. Either of two HSC subsets conferred disease when transplanted. Thus, flow cytometry can be used to observe the influence of abnormal JAK2 signaling on stem and progenitor subsets. Markers that similarly distinguish categories of human HSCs might be very valuable for monitoring such conditions. They could also serve as indicators of HSC fitness and suitability for transplantation.
    Full-text · Article · Apr 2014 · PLoS ONE
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    ABSTRACT: Common lymphoid progenitors (CLPs) are thought to represent major intermediates in the transition of hematopoietic stem cells (HSCs) to B lineage lymphocytes. However, it has been obvious for some time that CLPs are heterogeneous, and there has been controversy concerning their differentiation potential. We have now resolved four Flt3(+) CLP subsets that are relatively homogenous and capable of forming B cells. Differentiation potential and gene expression patterns suggest Flt3(+) CLPs lacking both Ly6D and RAG-1 are the least differentiated. In addition to B cells, they generate natural killer (NK) and dendritic cells (DCs). At the other extreme is a subset of the recently described Flt3(+) Ly6D(+) CLPs that have a history of RAG-1 expression and are B lineage restricted. These relatively abundant and potent CLPs were depleted within 48 hours of acute in vivo estrogen elevation, suggesting they descend from hormone regulated progenitors. This contrasts with the hormone insensitivity of other CLP subsets that include NK lineage progenitors. This progenitor heterogeneity and differentiation complexity may add flexibility in response to environmental changes. Expression of RAG-1 and display of Ly6D are both milestone events, but they are neither synchronized nor dependent on each other.
    Preview · Article · Aug 2013 · PLoS ONE

  • No preview · Article · Aug 2013 · Experimental Hematology
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    ABSTRACT: How hematopoietic stem cells (HSCs) produce particular lineages is insufficiently understood. We searched for key factors that direct HSC to lymphopoiesis. Comparing gene expression profiles for HSCs and early lymphoid progenitors revealed that Satb1, a global chromatin regulator, was markedly induced with lymphoid lineage specification. HSCs from Satb1-deficient mice were defective in lymphopoietic activity in culture and failed to reconstitute T lymphopoiesis in wild-type recipients. Furthermore, Satb1 transduction of HSCs and embryonic stem cells robustly promoted their differentiation toward lymphocytes. Whereas genes that encode Ikaros, E2A, and Notch1 were unaffected, many genes involved in lineage decisions were regulated by Satb1. Satb1 expression was reduced in aged HSCs with compromised lymphopoietic potential, but forced Satb1 expression partly restored that potential. Thus, Satb1 governs the initiating process central to the replenishing of lymphoid lineages. Such activity in lymphoid cell generation may be of clinical importance and useful to overcome immunosenescence.
    Full-text · Article · Jun 2013 · Immunity
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    Qingzhao Zhang · Ryuji Iida · Takafumi Yokota · Paul W Kincade
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    ABSTRACT: Purpose of review: Cells of the immune system are replaced in large numbers throughout life, and the underlying mechanisms have been extensively studied. Whereas the pace of discovery in this area is unprecedented, many questions remain, particularly with respect to lymphocyte formation. Recent findings: While transcription factors have long been a focus of investigation, microRNAs are also being implicated in lymphopoiesis. Lymphocytes are normally replaced in correct proportion to other blood cells, but ratios change dramatically during infections. Long-standing issues relating to T versus B lineage divergence remain but have been enriched with remarkable new findings about thymus seeding. There are indications that at least some age-related changes in lymphopoiesis may be reversible. Finally, knowledge obtained from studies of mice is slowly being extended to humans. Summary: We can now appreciate that new lymphoid progenitors are drawn from a heterogeneous collection of hematopoietic stem cells through asynchronous patterns of gene expression. Complex interactions then occur between the gene products, preparing lymphoid progenitors to respond to environmental cues. Whereas unique markers describe the process of lymphocyte formation in humans, fundamental information now available should suggest ways to promote rebound from chemotherapy or transplantation and reverse declines associated with aging.
    Full-text · Article · Apr 2013 · Current opinion in hematology
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    Paul W Kincade

    Preview · Article · Oct 2012 · The Journal of Immunology
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    ABSTRACT: A unique subset of CD86(-) HSCs was previously discovered in mice that were old or chronically stimulated with lipopolysaccharide. Functionally defective HSCs were also present in those animals, and we now show that CD86(-) CD150(+) CD48(-) HSCs from normal adult mice are particularly poor at restoring the adaptive immune system. Levels of the marker are high on all progenitors with lymphopoietic potential, and progressive loss helps to establish relations between progenitors corresponding to myeloid and erythroid lineages. CD86 represents an important tool for subdividing HSCs in several circumstances, identifying those unlikely to generate a full spectrum of hematopoietic cells.
    Preview · Article · Feb 2012 · Blood
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    Qingzhao Zhang · Ryuji Iida · Tomoyuki Shimazu · Paul W Kincade
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    ABSTRACT: The path from hematopoietic stem cells (HSCs) to functional B lymphocytes has long been appreciated as a basic model of differentiation, but much clinically relevant information has also been obtained. It is now possible to conduct single cell studies with increasingly high resolution, revealing that individual stem and progenitor cells differ from each other with respect to differentiation potential and fates. B lymphopoiesis is now seen as a gradual and unsynchronized process where progenitors eventually become B lineage restricted. Major milestones have been identified, but a precise sequence need not be followed and oscillation between states is possible. It is not yet clear if this versatility has survival value, but information is accumulating about infections and age-related changes.
    Preview · Article · Jan 2012 · Current opinion in immunology
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    T.C. Luis · M Ichii · M.H. Brugman · P Kincade · F J T Staal
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    ABSTRACT: A strict balance between self-renewal and differentiation of hematopoietic stem cells (HSCs) is required in order to maintain homeostasis, as well as to efficiently respond to injury and infections. Numbers and fate decisions made by progenitors derived from HSC must also be carefully regulated to sustain large-scale production of blood cells. The complex Wnt family of molecules generally is thought to be important to these processes, delivering critical signals to HSC and progenitors as they reside in specialized niches. Wnt proteins have also been extensively studied in connection with malignancies and are causatively involved in the development of several types of leukemias. However, studies with experimental animal models have produced contradictory findings regarding the importance of Wnt signals for normal hematopoiesis and lymphopoiesis. Here, we will argue that dose dependency of signaling via particular Wnt pathways accounts for much, if not all of this controversy. We conclude that there seems little doubt that Wnt proteins are required to sustain normal hematopoiesis, but are likely to be presented in carefully controlled gradients in a tissue-specific manner.
    Full-text · Article · Dec 2011 · Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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    ABSTRACT: Considerable information has accumulated about components of BM that regulate the survival, self-renewal, and differentiation of hematopoietic cells. In the present study, we investigated Wnt signaling and assessed its influence on human and murine hematopoiesis. Hematopoietic stem/progenitor cells (HSPCs) were placed on Wnt3a-transduced OP9 stromal cells. The proliferation and production of B cells, natural killer cells, and plasmacytoid dendritic cells were blocked. In addition, some HSPC characteristics were maintained or re-acquired along with different lineage generation potentials. These responses did not result from direct effects of Wnt3a on HSPCs, but also required alterations in the OP9 cells. Microarray, PCR, and flow cytometric experiments revealed that OP9 cells acquired osteoblastic characteristics while down-regulating some features associated with mesenchymal stem cells, including the expression of angiopoietin 1, the c-Kit ligand, and VCAM-1. In contrast, the production of decorin, tenascins, and fibromodulin markedly increased. We found that at least 1 of these extracellular matrix components, decorin, is a regulator of hematopoiesis: upon addition of this proteoglycan to OP9 cocultures, decorin caused changes similar to those caused by Wnt3a. Furthermore, hematopoietic stem cell numbers in the BM and spleen were elevated in decorin-knockout mice. These findings define one mechanism through which canonical Wnt signaling could shape niches supportive of hematopoiesis.
    Full-text · Article · Nov 2011 · Blood
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    ABSTRACT: Hematopoietic stem cells (HSC) can be harmed by disease, chemotherapy, radiation, and normal aging. We show in this study that damage also occurs in mice repeatedly treated with very low doses of LPS. Overall health of the animals was good, and there were relatively minor changes in marrow hematopoietic progenitors. However, HSC were unable to maintain quiescence, and transplantation revealed them to be myeloid skewed. Moreover, HSC from treated mice were not sustained in serial transplants and produced lymphoid progenitors with low levels of the E47 transcription factor. This phenomenon was previously seen in normal aging. Screening identified mAbs that resolve HSC subsets, and relative proportions of these HSC changed with age and/or chronic LPS treatment. For example, minor CD150(Hi)CD48(-) populations lacking CD86 or CD18 expanded. Simultaneous loss of CD150(Lo/-)CD48(-) HSC and gain of the normally rare subsets, in parallel with diminished transplantation potential, would be consistent with age- or TLR-related injury. In contrast, HSC in old mice differed from those in LPS-treated animals with respect to VCAM-1 or CD41 expression and lacked proliferation abnormalities. HSC can be exposed to endogenous and pathogen-derived TLR ligands during persistent low-grade infections. This stimulation might contribute in part to HSC senescence and ultimately compromise immunity.
    Full-text · Article · Mar 2011 · The Journal of Immunology
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    Paul W Kincade
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    ABSTRACT: Hematopoietic stem cells (HSCs) sustain blood formation throughout life and their integrity depends on residence in specialized niches within bone marrow. However, there are considerable technical problems associated with sectioning lipid-rich, bone-encapsulated tissue while preserving distinctive niche markers and unambiguously identifying HSCs. For those and other reasons, precise information about the cellular and molecular composition of those niches has been difficult to obtain. Fortunately, those hurdles have been overcome, and a new picture is emerging about how the factory that marrow represents can adapt to circumstances.
    Preview · Article · Sep 2010 · Immunity
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    ABSTRACT: Requirements for human B lymphopoiesis are still poorly understood, and that has hampered investigation of differentiation events. For example, there are few cell surface antigens that can be used as milestones of lineage progression. The CD10 ectoenzyme is one such marker and has been used to define CLP, but we found substantial tissue specific variations in CD10 levels, and there was no information about how that corresponded to differentiation options. The aim of the present study was to use recently developed culture methods to assess the nature and differentiation potential of progenitors sorted according to CD10 density from umbilical cord blood (CB), adult bone marrow (BM) or G-CSF mobilized peripheral blood (PB). Many CD34(+) cells in BM express high levels of CD10, while low or low/negative CD10 densities were found on CD34(+) cells in CB or G-CSF mobilized PB, respectively. The relative abundance of CD10(Lo) versus CD10(Hi) cells only accounts for some CB versus BM differences. Almost all of the CD34(+) CD10(Hi) cells expressed CD19 and lymphocyte transcription factors and corresponded to loss of myeloid potential. A high degree of immunoglobulin D(H)-J(H) gene rearrangements was characteristic only of the CD10(Hi) subset. In contrast, the CD34(+) CD10(Lo) progenitors efficiently produced plasmacytoid and conventional dendritic cells as well as myeloid cells. These findings suggest a positive correlation between CD10 density and degree of differentiation. Although freshly isolated CD34(+) CD10(Hi) cells were in cycle, those from CB or BM expanded poorly in culture, suggesting regulators of populations remain to be discovered. Steps in human B lymphopoiesis have not been sufficiently studied, and we now show that increased CD10 expression corresponds to differentiation potential and stage. CD34(+) CD10(Hi) progenitors are obviously in the B lineage but may have progressed beyond the point where they can be expanded in culture.
    Full-text · Article · Sep 2010 · PLoS ONE
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    ABSTRACT: B-cell regulator of immunoglobulin heavy chain transcription (Bright)/ARID3a, an A+T-rich interaction domain protein, was originally discovered in B lymphocyte lineage cells. However, expression patterns and high lethality levels in knockout mice suggested that it had additional functions. Three independent lines of evidence show that functional inhibition of Bright results in increased developmental plasticity. Bright-deficient cells from two mouse models expressed a number of pluripotency-associated gene products, expanded indefinitely, and spontaneously differentiated into cells of multiple lineages. Furthermore, direct knockdown of human Bright resulted in colonies capable of expressing multiple lineage markers. These data suggest that repression of this single molecule confers adult somatic cells with new developmental options.
    Full-text · Article · Sep 2010 · Stem Cells
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    ABSTRACT: Technical advances have made it possible to separate hematopoietic tissues such as the bone marrow into ever smaller populations, complicating our understanding of immune system replenishment. Patterns of surface marker expression and transcription profiles as well as results obtained with reporter mice suggest that lymphopoietic cells are not closely synchronized, and there is considerable cell to cell variation. Loss of differentiation options is gradual, and ultimate fate can be established at different stages of lineage progression. For example, individual hematopoietic stem cells can be biased such that some are very poor sources of lymphocytes as contrasted to ones with balanced outputs. Still other hematopoietic stem cells are effective at generating B and T cells but are defective with respect to expansion and difficult to distinguish from early lymphoid progenitors. That diversity carries forward to later events, and similar appearing cells in the immune system can arise from alternate differentiation pathways. In fact, new categories of lymphoid progenitors are still being discovered. Heterogeneity provides adaptability as hematopoiesis can be dramatically altered during infections, influencing numbers and types of cells that are produced.
    Full-text · Article · Sep 2010 · Immunological Reviews
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    ABSTRACT: Regulation of apoptosis and cell cycle progression plays an essential role in the maintenance of B-cell homeostasis, because a fine balance of survival and expansion is critical for preventing lymphocytic disorders. Although remarkable progress in understanding B-cell development has been achieved, much less is known concerning niches that are critical to the maintenance of B-cell homeostasis. Leptin has recently been recognized to be important for modulating the immune responses, but it has remained unclear how leptin signaling influences B-cell physiology. A variety of lymphocytic malignancies have been reported to be linked to leptin, and therefore it is necessary to elucidate the mechanisms involved. Here we demonstrate that leptin promotes B-cell homeostasis by inhibiting apoptosis and by inducing cell cycle entry through the activation of expressions of B-cell CLL/lymphoma 2 (Bcl-2) and cyclin D1. We further show that leptin can induce Bcl-2 and cyclin D1 expression by two pathways, including the direct activation of their promoters and suppression of microRNAs (miRNAs) that target their putative 3'untranslated regions. Amplification of these leptin-modulated miRNAs inhibited B lymphoma cell growth. These findings provide insights into mechanisms for leptin regulation of the humoral immune system and suggest new therapeutic strategies for leptin receptor expressing malignancies.
    Full-text · Article · Aug 2010 · Proceedings of the National Academy of Sciences

Publication Stats

15k Citations
2,042.96 Total Impact Points


  • 1984-2015
    • Oklahoma Medical Research Foundation
      • Immunobiology and Cancer Program
      Oklahoma City, Oklahoma, United States
  • 2011
    • University of Pittsburgh
      • Department of Immunology
      Pittsburgh, PA, United States
  • 2003-2010
    • Oklahoma City University
      Oklahoma City, Oklahoma, United States
  • 1985-2008
    • University of Oklahoma Health Sciences Center
      • • Department of Microbiology and Immunology
      • • Section of Infectious Diseases
      • • Department of Pediatrics
      Oklahoma City, OK, United States
  • 2006
    • University of Toronto
      Toronto, Ontario, Canada
  • 1977-2006
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 2004
    • Brown University
      Providence, Rhode Island, United States
  • 2001-2003
    • Osaka University
      • • Department of Internal Medicine
      • • Graduate School of Medicine
      Suika, Ōsaka, Japan
  • 2002
    • University of Chicago
      • Department of Pathology
      Chicago, Illinois, United States
  • 1988-2002
    • University of California, Los Angeles
      • Molecular Biology Institute
      Los Ángeles, California, United States
  • 1992-1993
    • Salk Institute
      • Cancer Biology Laboratory
      La Jolla, California, United States
    • The Ohio State University
      • Department of Surgery
      Columbus, OH, United States
    • McGill University
      • Department of Anatomy and Cell Biology
      Montréal, Quebec, Canada
  • 1991
    • National Institutes of Health
      • Branch of Experimental Immunology
      Bethesda, MD, United States
    • Northern Inyo Hospital
      BIH, California, United States
  • 1989
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem District, Israel
  • 1982
    • The Rockefeller University
      New York, New York, United States
  • 1975
    • Royal Melbourne Hospital
      Melbourne, Victoria, Australia