Thymocytes may persist and differentiate without any input from bone marrow progenitors

Peaudecerf, Laetitia; Lemos, Sara; Galgano, Alessia; Krenn, Gerald; Vasseur, Florence; Santo, James P. Di; Ezine, Sophie; Rocha, Bénédita

doi:10.1084/jem.20120845

Cited by 83 publications

(114 citation statements)

References 27 publications

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“…7H). These data suggest that although MCs from all tested tissues constitutively express genes predicted to support HSCs, these genes are expressed at higher levels in MCs from organs that harbor hematolymphoid progenitors with self-renewal potential (i.e., the bone and thymus) (31,61,62 (28). We found that genes coding for these seven receptors were expressed (RPKM .2) in at least one population of hematopoietic progenitors (Fig.…”

Section: Mcs and The Hsc Nichementioning

confidence: 68%

Thymic Mesenchymal Cells Have a Distinct Transcriptomic Profile

Patenaude

Perreault

2016

The Journal of Immunology

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In order to understand the role of mesenchymal cells (MCs) in the adult thymus, we performed whole transcriptome analyses of primary thymic, bone, and skin MCs. These three MC populations shared expression of 2850 core MC genes involved in generic processes including interactions with tissue-resident macrophages. Moreover, we discovered that 2036 genes were differentially expressed, by at least 5-fold, in the three MC populations. Genes preferentially expressed in thymic MCs are instrumental in clearance of apoptotic thymocytes by macrophages, maintenance of a noninflammatory milieu, and attraction-expansion of thymocyte progenitors. Thymic and bone MCs share other sets of differentially expressed genes implicated in resolution of inflammation and expansion of hematolymphoid progenitors. Consistent with the fact that thymic and skin MCs have to support epithelial cells, they express at higher levels genes mediating epithelial cell adhesion to basement membrane and mesenchymal–epithelial cross-talk. Differentially expressed genes preferentially expressed by bone MCs are connected to formation and remodeling of bone, whereas those preferentially expressed in skin MCs are involved in skin and hair follicle homeostasis. We conclude that MCs from different organs display substantial heterogeneity and that the transcriptome of thymic MCs is exquisitely suited for interactions with epithelial and hematolymphoid cells in an environment with a high apoptosis rate.

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Section: Mcs and The Hsc Nichementioning

confidence: 68%

Thymic Mesenchymal Cells Have a Distinct Transcriptomic Profile

Patenaude

Perreault

2016

The Journal of Immunology

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“…29,43 Recent studies have revealed that under conditions of blocked thymic entry, normal thymic progenitors exhibit self-renewal capabilities. 44,45 We find the leukemic DN3 thymic progenitors enriched in disease potential 13 and hypothesize that sustained activation of the Notch1-c-Myc pathway in this progenitor cell type results in extensive proliferative capacity while retaining the ability to self-renew and differentiate into double-positive leukemic blasts.…”

Section: Discussionmentioning

confidence: 90%

c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells

Roderick

Tesell

Shultz

et al. 2014

Blood

135

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“…Furthermore, even in the absence of irradiation, elegant experiments showed that intrathymically injected BM progenitors do not sustain long-term thymopoiesis in wild-type (WT) mice where there is a normal importation of precursors [23]. However, recent studies, performed by our group and others, have shown that in immunodeficient mice, under conditions where competitive BM progenitors and/or early thymocyte progenitors are restricted, long-term thymus-autonomous T-cell differentiation can occur [57][58][59]. Thus, long-term thymopoiesis from injected progenitors can occur in the thymus under conditions where there is an available progenitor thymic ''niche'' (Fig.…”

Section: (B)mentioning

confidence: 99%

“…derived thymic settling cells that normally seed the thymus [51], with the former harboring T, B, granulocyte-macrophage (GM), and megakaryocyte-erythroid potential [61]. Furthermore, it has recently been elegantly shown that thymusautonomous T-cell differentiation can be sustained in mice with combined mutations in Rag2 together with either c-Kit or cc [58,59]. These studies differed from those described above in that thymic lobes from newborn WT mice, rather than HSC, were transferred into immunodeficient mice with a paucity of their own bone marrow progenitors (Fig.…”

Section: (B)mentioning

confidence: 99%

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

2013

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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.

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Thymocytes may persist and differentiate without any input from bone marrow progenitors

Abstract: New thymus transplant experiments reveal that in the absence of competing bone marrow progenitors, existing thymocytes can self-renew, guaranteeing thymus cellularity and the rapid reconstitution of the peripheral T cell pools.

Cited by 83 publications

References 27 publications

Thymic Mesenchymal Cells Have a Distinct Transcriptomic Profile

Thymic Mesenchymal Cells Have a Distinct Transcriptomic Profile

c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells

Concise Review: Hematopoietic Stem Cell Transplantation: Targeting the Thymus

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