P W Kincade

Memorial Sloan-Kettering Cancer Center, New York, New York, United States

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Publications (305)2136.39 Total impact

  • No preview · Article · Sep 2015 · Experimental Hematology
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    [Show abstract] [Hide abstract] 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
  • [Show abstract] [Hide abstract] 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
    [Show abstract] [Hide abstract] 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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    [Show abstract] [Hide abstract] 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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    Dataset: Figure S6
    [Show abstract] [Hide abstract] ABSTRACT: Developmental model of CLPs. Using Flt3, Ly6D and RAG-1/tdRFP, we resolved CLPs into six subsets. The two Flt3− subsets were heterogeneous and showed poor B lymphocyte lineage potential. They likely include recently described pNKP and, the Flt3− tdRFP− subset could differentiate into NK and DCs. Among the four Flt3+ subsets, cells lacking RAG-1 and Ly6D generated B lineage cells, NK and DCs, and they were also ancestors for the other three Flt3+ CLP subsets. Ly6D and RAG-1 each marked B lineage progression. However, they were expressed independently and asynchronously. The convergence of these two markers eventually labeled the most potent and immediate of B cell precursors. Major differentiation pathways are indicated by bold arrows, while dotted lines indicate areas that merit additional study. (TIF)
    Preview · Dataset · Aug 2013
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    [Show abstract] [Hide abstract] 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
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    Dataset: Figure S3
    [Show abstract] [Hide abstract] ABSTRACT: The expression of lineage associated genes correlates with differentiation potential. The six CLP subsets were isolated as above, and then mRNA was extracted and used for real-time PCR. The transcript levels of indicated genes were normalized based on GAPDH expression, and shown as relative expression levels ± EM calculated from at least three experiments. The expression levels of the Flt3+ Ly6D− RAG1/tdRFP− subset was used as baseline (valued as 1) and the expression levels of other populations were calculated relative to that baseline. (TIF)
    Preview · Dataset · Aug 2013
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    Dataset: Figure S1
    [Show abstract] [Hide abstract] ABSTRACT: The abundance and potency of B lymphocyte lineage progenitors in CLPs. The width of each pie slice is proportional to the average percentages that each CLP subset represents. The height of each pie slice is proportional to the average B lineage cell yield in 12 day cultures. The data used to prepare this graphic were separately shown above in Figures 1 and 2. (TIF)
    Preview · Dataset · Aug 2013
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    Dataset: Figure S2
    [Show abstract] [Hide abstract] ABSTRACT: B lymphopoietic potential of CLP subsets. Indicated numbers (8 to 24 replicates per dilution) of cells from selected progenitor populations were sorted and cultured under stromal cell-free, serum-free conditions in the presence of IL-7, SCF and Flt3 ligand. Cells were harvested 13 days later and analyzed for B220+ CD19+ B lineage cell production. (TIF)
    Preview · Dataset · Aug 2013
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    Dataset: Figure S4
    [Show abstract] [Hide abstract] ABSTRACT: Lineage potentials of CLP subsets in OP9 co-cultures. The six indicated CLP subsets (1500 cells per well) were sorted and cultured on monolayers of OP9 stromal cells in the presence of SCF, IL-7 and Flt3 ligand. Cells were harvested and analyzed after 7 or 12 days (data not shown) of culture. The data shown represents one of five independent experiments. (A) Cells were analyzed for B220+ CD19+ B lineage cell production. (B) Cells were analyzed for NK1.1+ NK lineage cell production. (TIF)
    Preview · Dataset · Aug 2013
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    Dataset: Figure S5
    [Show abstract] [Hide abstract] ABSTRACT: T lineage potential of CLP subsets. (A) Sorted CLP subsets, MPP and thymic ETP were cultured on OP9-DL1 stromal cells in media containing Flt3 ligand and IL-7 for 7 and 12 days. Cells were harvested and analyzed for T lineage cell (CD45.2+ CD44+ CD25+) yield. (B) mRNA was extracted from CLP subsets, HSCs and thymic ETP and then used as templates for cDNA synthesis. Real-time PCR for the indicated genes was performed. The transcript levels of indicated genes were normalized based on GAPDH expression, and shown as relative expression levels ±SEM calculated from three experiments. The gene expression levels of HSC or Flt3− Ly6D− RAG-1/tdRFP− CLPs were used as baselines. (TIF)
    Preview · Dataset · Aug 2013
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    Preview · Dataset · Aug 2013
  • No preview · Article · Aug 2013 · Experimental Hematology
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    [Show abstract] [Hide abstract] 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
    [Show abstract] [Hide abstract] 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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    [Show abstract] [Hide abstract] 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
    [Show abstract] [Hide abstract] 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
    [Show abstract] [Hide abstract] 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

Publication Stats

15k Citations
2,136.39 Total Impact Points

Institutions

  • 2006
    • Memorial Sloan-Kettering Cancer Center
      New York, New York, United States
  • 2004-2006
    • University of Toronto
      Toronto, Ontario, Canada
    • Brown University
      Providence, Rhode Island, United States
  • 2003-2006
    • Oklahoma City University
      Oklahoma City, Oklahoma, United States
    • Kumamoto University
      Kumamoto, Kumamoto, Japan
  • 2002
    • Osaka University
      Suika, Ōsaka, Japan
  • 2001
    • Oklahoma Medical Research Foundation
      • Immunobiology and Cancer Program
      Oklahoma City, OK, United States
  • 1993
    • Salk Institute
      • Cancer Biology Laboratory
      La Jolla, California, United States