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Timothy J. Davies

Bio: Timothy J. Davies is an academic researcher from University of Oxford. The author has contributed to research in topics: Induced pluripotent stem cell & Embryonic stem cell. The author has an hindex of 12, co-authored 22 publications receiving 2333 citations. Previous affiliations of Timothy J. Davies include National Institute for Health Research.

Papers
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Journal ArticleDOI
12 Jul 2007-Nature
TL;DR: It is shown that cell lines can be derived from the epiblast, a tissue of the post-implantation embryo that generates the embryo proper, and interrogated to understand how pluripotent cells generate distinct fates during early development.
Abstract: The application of human embryonic stem (ES) cells in medicine and biology has an inherent reliance on understanding the starting cell population. Human ES cells differ from mouse ES cells and the specific embryonic origin of both cell types is unclear. Previous work suggested that mouse ES cells could only be obtained from the embryo before implantation in the uterus. Here we show that cell lines can be derived from the epiblast, a tissue of the post-implantation embryo that generates the embryo proper. These cells, which we refer to as EpiSCs (post-implantation epiblast-derived stem cells), express transcription factors known to regulate pluripotency, maintain their genomic integrity, and robustly differentiate into the major somatic cell types as well as primordial germ cells. The EpiSC lines are distinct from mouse ES cells in their epigenetic state and the signals controlling their differentiation. Furthermore, EpiSC and human ES cells share patterns of gene expression and signalling responses that normally function in the epiblast. These results show that epiblast cells can be maintained as stable cell lines and interrogated to understand how pluripotent cells generate distinct fates during early development.

2,134 citations

Journal ArticleDOI
14 Apr 2011-Blood
TL;DR: It is demonstrated, for the first time, that human iPS cells are able to undergo hematopoiesis that contributes to the B-cell lymphoid lineage.

76 citations

Journal ArticleDOI
TL;DR: The ability to generate a potentially unlimited source from iPS cells offers the possibility of harnessing their capacity for cross-priming of cytotoxic T lymphocytes for the induction of tumour-specific immune responses.
Abstract: Monocyte-derived dendritic cells (moDC) have been widely used in cancer immunotherapy but show significant donor-to-donor variability and low capacity for the cross-presentation of tumour-associated antigens (TAA) to CD8(+) T cells, greatly limiting the success of this approach. Given recent developments in induced pluripotency and the relative ease with which induced pluripotent stem (iPS) cell lines may be generated from individuals, we have succeeded in differentiating dendritic cells (DC) from human leukocyte antigen (HLA)-A(*)0201(+) iPS cells (iPS cell-derived DC (ipDC)), using protocols compliant with their subsequent clinical application. Unlike moDC, a subset of ipDC was found to coexpress CD141 and XCR1 that have been shown previously to define the human equivalent of mouse CD8α(+) DC, in which the capacity for cross-presentation has been shown to reside. Accordingly, ipDC were able to cross-present the TAA, Melan A, to a CD8(+) T-cell clone and stimulate primary Melan A-specific responses among naive T cells from an HLA-A(*)0201(+) donor. Given that CD141(+)XCR1(+) DC are present in peripheral blood in trace numbers that preclude their clinical application, the ability to generate a potentially unlimited source from iPS cells offers the possibility of harnessing their capacity for cross-priming of cytotoxic T lymphocytes for the induction of tumour-specific immune responses.

58 citations

Journal ArticleDOI
TL;DR: Protocols for the directed differentiation of human iPSCs into a mixed population of CD11c+ DCs are described, providing access to a novel source of DCs analogous to the CD141+ subset under steady-state conditions in vivo and may find utility in the treatment of a range of disease states requiring the establishment of immunological tolerance.
Abstract: The advent of induced pluripotent stem cells (iPSCs) has begun to revolutionize cell therapy by providing a convenient source of rare cell types not normally available from patients in sufficient numbers for therapeutic purposes. In particular, the development of protocols for the differentiation of populations of leukocytes as diverse as naive T cells, macrophages, and natural killer cells provides opportunities for their scale-up and quality control prior to administration. One population of leukocytes whose therapeutic potential has yet to be explored is the subset of conventional dendritic cells (DCs) defined by their surface expression of CD141. While these cells stimulate cytotoxic T cells in response to inflammation through the cross-presentation of viral and tumor-associated antigens in an MHC class I-restricted manner, under steady-state conditions CD141+ DCs resident in interstitial tissues are focused on the maintenance of homeostasis through the induction of tolerance to local antigens. Here, we describe protocols for the directed differentiation of human iPSCs into a mixed population of CD11c+ DCs through the spontaneous formation of embryoid bodies and exposure to a cocktail of growth factors, the scheduled withdrawal of which serves to guide the process of differentiation. Furthermore, we describe the enrichment of DCs expressing CD141 through depletion of CD1c+ cells, thereby obtaining a population of "untouched" DCs unaffected by cross-linking of surface CD141. The resulting cells display characteristic phagocytic and endocytic capacity and acquire an immunostimulatory phenotype following exposure to inflammatory cytokines and toll-like receptor agonists. Nevertheless, under steady-state conditions, these cells share some of the tolerogenic properties of tissue-resident CD141+ DCs, which may be further reinforced by exposure to a range of pharmacological agents including interleukin-10, rapamycin, dexamethasone, and 1α,25-dihydoxyvitamin D3. Our protocols therefore provide access to a novel source of DCs analogous to the CD141+ subset under steady-state conditions in vivo and may, therefore, find utility in the treatment of a range of disease states requiring the establishment of immunological tolerance.

47 citations

Journal ArticleDOI
TL;DR: The second polar body (Pb) provides an enduring marker of the animal pole of the zygote, thereby revealing that the axis of bilateral symmetry of the early blastocyst is aligned with theZygote's animal-vegetal axis.
Abstract: The second polar body (Pb) provides an enduring marker of the animal pole of the zygote, thereby revealing that the axis of bilateral symmetry of the early blastocyst is aligned with the zygote's animal-vegetal axis. That this relationship is biologically significant appeared likely when subsequent studies showed that the equator of the blastocyst tended to correspond with the plane of first cleavage. However, this cleavage plane varies both with respect to the position of the second Pb and to the distribution of components of the fertilizing sperm that continue to mark the point where it entered the egg. It also maps too variably on the blastocyst to play a causal role in early patterning. The zygote has been found transiently to exhibit bilateral symmetry before regaining an essentially spherical shape prior to first cleavage. Marking experiments indicate that the plane of bilateral symmetry of the blastocyst is aligned with, and the plane of first cleavage is typically orthogonal to, the zygote's bilateral plane. The bilateral symmetry of the zygote bears no consistent relationship either to the point of sperm entry or to the distribution of the pronuclei, and may therefore be a manifestation of intrinsic organization of the egg. Finally, the two-cell blastomere inheriting the sperm entry point has not been found to differ consistently in fate from the one that does not.

38 citations


Cited by
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Journal ArticleDOI
30 Nov 2007-Cell
TL;DR: It is demonstrated that iPS cells can be generated from adult human fibroblasts with the same four factors: Oct3/4, Sox2, Klf4, and c-Myc.

18,175 citations

Journal ArticleDOI
TL;DR: This work generated induced pluripotent stem cells capable of germline transmission from murine somatic cells by transd, and demonstrated the ability of these cells to reprogram into patient-specific and disease-specific stem cells.
Abstract: If it were possible to reprogram differentiated human somatic cells into a pluripotent state, patient-specific and disease-specific stem cells could be developed. Previous work generated induced pluripotent stem (iPS) cells capable of germline transmission from murine somatic cells by transd

4,034 citations

Journal ArticleDOI
TL;DR: Noggin/SB431542-based neural induction should facilitate the use of hES and hiPS cells in regenerative medicine and disease modeling and obviate the need for protocols based on stromal feeders or embryoid bodies.
Abstract: Current neural induction protocols for human embryonic stem (hES) cells rely on embryoid body formation, stromal feeder co-culture or selective survival conditions. Each strategy has considerable drawbacks, such as poorly defined culture conditions, protracted differentiation and low yield. Here we report that the synergistic action of two inhibitors of SMAD signaling, Noggin and SB431542, is sufficient to induce rapid and complete neural conversion of >80% of hES cells under adherent culture conditions. Temporal fate analysis reveals the appearance of a transient FGF5(+) epiblast-like stage followed by PAX6(+) neural cells competent to form rosettes. Initial cell density determines the ratio of central nervous system and neural crest progeny. Directed differentiation of human induced pluripotent stem (hiPS) cells into midbrain dopamine and spinal motoneurons confirms the robustness and general applicability of the induction protocol. Noggin/SB431542-based neural induction should facilitate the use of hES and hiPS cells in regenerative medicine and disease modeling and obviate the need for protocols based on stromal feeders or embryoid bodies.

3,152 citations

Journal ArticleDOI
TL;DR: It is proposed that two phases of pluripotency can be defined: naive and primed, and this distinction extends to pluripotent stem cells derived from embryos or by molecular reprogramming ex vivo.

1,640 citations

Journal ArticleDOI
20 Dec 2007-Nature
TL;DR: By genetic deletion, it is shown that, although they are prone to differentiate, embryonic stem cells can self-renew indefinitely in the permanent absence of Nanog, and it is surmised that Nanog stabilizes embryonicstem cells in culture by resisting or reversing alternative gene expression states.
Abstract: Nanog is a divergent homeodomain protein found in mammalian pluripotent cells and developing germ cells. Deletion of Nanog causes early embryonic lethality, whereas constitutive expression enables autonomous self-renewal of embryonic stem cells. Nanog is accordingly considered a core element of the pluripotent transcriptional network. However, here we report that Nanog fluctuates in mouse embryonic stem cells. Transient downregulation of Nanog appears to predispose cells towards differentiation but does not mark commitment. By genetic deletion we show that, although they are prone to differentiate, embryonic stem cells can self-renew indefinitely in the permanent absence of Nanog. Expanded Nanog null cells colonize embryonic germ layers and exhibit multilineage differentiation both in fetal and adult chimaeras. Although they are also recruited to the germ line, primordial germ cells lacking Nanog fail to mature on reaching the genital ridge. This defect is rescued by repair of the mutant allele. Thus Nanog is dispensible for expression of somatic pluripotency but is specifically required for formation of germ cells. Nanog therefore acts primarily in construction of inner cell mass and germ cell states rather than in the housekeeping machinery of pluripotency. We surmise that Nanog stabilizes embryonic stem cells in culture by resisting or reversing alternative gene expression states.

1,540 citations