Transcription from the RAG1 Locus Marks the Earliest Lymphocyte Progenitors in Bone Marrow

Igarashi, Hideya; Gregory, Sophia C.; Yokota, Takafumi; Sakaguchi, Nobuo; Kincade, Paul W.

doi:10.1016/s1074-7613(02)00366-7

Cited by 401 publications

(491 citation statements)

References 75 publications

(1 reference statement)

Supporting

Mentioning

467

Contrasting

Unclassified

Order By: Relevance

“…Previous studies showing changes in lineage potentials correlated, for instance, to changes in recombination activating gene 1 (Rag1) and Vcam-1 expression, providing findings compatible with the last scenario, 12,13,21 but as clonogenic studies were not performed, it remains possible that the observed changes in lineage potentials reflected altered ratios of a mixture of progenitors of multiple lineages, rather than gradual changes in potentials for multiple lineages within multipotent progenitor cells.…”

Section: Introductionmentioning

confidence: 81%

Down-regulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential

Luc

Anderson

Kharazi

et al. 2008

Blood

View full text Add to dashboard Cite

IntroductionWhereas considerable knowledge has been gained with regard to the identity and roles of extrinsic and intrinsic regulators of blood lineage development, much less is known about the molecular mechanisms regulating lineage commitment of hematopoietic stem cells (HSCs). 1,2 Unraveling the involved molecular determinants and mechanisms of lineage restriction will be facilitated by, and most likely depend on, a more complete understanding of the cellular pathways of the lineage restriction process from pluripotent HSCs to lineage-restricted progenitor cells.It remains unclear and debated 2-4 exactly how the lineage commitment process from pluripotent HSCs to lineage-restricted progenitors occurs in adult bone marrow (BM), and even unequivocal evidence for one such pathway would not exclude the existence of alternative routes for HSC lineage commitment. In the prevailing model of HSC lineage commitment, 1-3 HSCs (long-term and short-term) and multipotent progenitors (MPPs) distinguish themselves from each other, only through gradual loss of self-renewal potential while sustaining the same degree of pluripotentiality, with the first lineage commitment event resulting in a strict separation of myelopoiesis and lymphopoiesis. This model for HSC lineage commitment was supported by the identification of common myeloid and common lymphoid progenitors (CMPs and CLPs, respectively). 5,6 However, the degree to which the identified CMPs and CLPs represent obligatory or even main intermediates for myeloid and lymphoid development in adult hematopoiesis remains to be established.Although conclusively established for long-term HSCs (LTHSCs), 7,8 the existence of short-term HSCs (ST-HSCs) and MPPs in the BM Lin Ϫ Sca-1 ϩ Kit ϩ (LSK) stem and primitive progenitor cell compartment, with sustained pluripotentiality has yet to be demonstrated at the single cell level. 3 Rather, more recent studies have uncovered considerable heterogeneity in the LSK MPP compartment. Through the use of different but overlapping markers such as FMS-like tyrosine kinase 3 (Flt3), 9-11 vascular cell adhesion molecule-1 (Vcam-1), 12,13 and an Ikaros-reporter, 14 the existence of lymphoid-primed MPPs (LMPPs) with combined granulocyte/monocyte (GM) and lymphoid potentials, but little or no megakaryocyte (Mk)/erythroid (E) potentials has been proposed. 3,10,12,14,15 Further, molecular analysis of putative LMPPs show down-regulated transcriptional priming of genes specific for the MkE lineage, and up-regulation of lymphoid-specific genes, not yet expressed in HSCs. 15,16 The identification of a putative LMPP, representing the earliest lineage-restricted lympho-myeloid progenitor identified in adult hematopoiesis, has provided a potential avenue toward uncovering alternative HSC lineage commitment pathways. 2,3,17 However, the existence of the LMPP remains contentious, 2,3,[18][19][20] largely reflecting functional heterogeneity of phenotypically defined candidate LMPPs. 9,10,[12][13][14] While the evidence for a large fraction of LSKFlt3 hi BM cell...

show abstract

Section: Introductionmentioning

confidence: 81%

Down-regulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential

Luc

Anderson

Kharazi

et al. 2008

Blood

View full text Add to dashboard Cite

show abstract

“…In mice, multipotent progenitors (MPP), retaining both myeloid and lymphoid potential, are generated from HSC and are characterized by the upregulation of the Fms-like tyrosine kinase receptor 3 (Flt3/CD135; resulting in LSK/CD135þ cells) [36]. Subsets of MPP, characterized by expression of molecules such as RAG-1 [37] and Lselectin [38], can also give rise to thymic precursors. Common lymphocyte precursors (CLPs) are more committed in that they lack myeloid potential and these progenitors can be distinguished as CLP-1 (Lin-Sca-1þCD117þ/loCD127þCD135þ) [39] and CLP-2 (Lin-Sca-1þCD117-CD127þCD135þB220þ) [40].…”

Section: Hematopoietic Precursor Differentiation Within the Thymusmentioning

confidence: 99%

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

2013

View full text Add to dashboard Cite

Allogeneic hematopoietic stem cell (HSC) transplantation can cure patients suffering from diverse genetic and acquired diseases as well as cancers. Nevertheless, under conditions where T-cell reconstitution is critical, the entry of donor progenitors into the thymus remains a major bottleneck. It is assumed that following the intravenous injection of HSC, they first home to the BM. More committed progenitors can then be exported to the thymus in response to a myriad of signals regulating thymus seeding. Notably although, the thymus is not continually receptive to the import of hematopoietic progenitors. Furthermore, as stem cells with self-renewing capacity do not take up residence in the thymus under physiological conditions, the periodic colonization of the thymus is essential for the sustained differentiation of T lymphocytes. As such, we and others have invested significant efforts into exploring avenues that might foster a long-term thymus-autonomous differentiation. Here, we review strategic approaches that have resulted in long-term T-cell differentiation in immunodeficient (SCID) mice, even across histocompatibility barriers. These include the forced thymic entry of BM precursors by their direct intrathymic injection as well as the transplantation of neonatal thymi. The capacity of the thymus to support hematopoietic progenitors with renewal potential will hopefully promote the development of new therapeutic strategies aimed at enhancing T-cell differentiation in patients undergoing HSC transplantation.

show abstract

“…Since c-kit-deficient mice show a dramatic impairment of B cell generation, the requirement for c-kit in B cell development must be in a cell upstream of the EPLM. A potential candidate for such a cell would be the recently described early lymphocyte precursor [16].…”

Section: The Differentiation Of Eplm Into the T But Not B Cell Lineagmentioning

confidence: 99%

Critical role for c‐kit (CD117) in T cell lineage commitment and early thymocyte development in vitro

Massa¹,

Balc̆iūnaite²,

Ceredig³

et al. 2006

Eur J Immunol

View full text Add to dashboard Cite

The precise roles played by the transmembrane receptor tyrosine kinase c-kit and its ligand stem cell factor in early T cell development are difficult to study. Using cloned Pax5-deficient progenitor B cells, we show that following Notch signaling, which induces their commitment to the T cell developmental pathway, c-kit expression is rapidly up-regulated at both the transcriptional and cell surface level. Using either an anti-c-kit monoclonal antibody or Gleevec, a pharmacological inhibitor of c-kit signaling, we show that the Notch-induced T cell differentiation of either Pax5-deficient progenitor B cells, or the equivalent cell from the bone marrow of normal mice, is strictly dependent on c-kit signaling, whereas the differentiation of normal progenitors into the B cell lineage is not. Moreover, we show that the Notch and IL-7 signalinginduced proliferation and differentiation of CD44 + CD25 -c-kit high and CD44 + CD25 + ckit high thymocytes along the T cell, but not natural killer cell or macrophage, pathway also requires c-kit signaling, whereas the Notch-induced proliferation and differentiation of CD44 -CD25 + c-kit int cells along the T cell pathway is independent of c-kit. These results further highlight the complex inter-relationships existing between c-kit, Notch and IL-7 receptor signaling that control the proliferation and differentiation of early T cell progenitors.

show abstract

Transcription from the RAG1 Locus Marks the Earliest Lymphocyte Progenitors in Bone Marrow

Cited by 401 publications

References 75 publications

Down-regulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential

Down-regulation of Mpl marks the transition to lymphoid-primed multipotent progenitors with gradual loss of granulocyte-monocyte potential

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

Critical role for c‐kit (CD117) in T cell lineage commitment and early thymocyte development in vitro

Contact Info

Product

Resources

About