Rapid Thymic Reconstitution Following Bone Marrow Transplantation in Neonatal Mice is VEGF-Dependent

Cuddihy, Andrew; Suterwala, Batul T.; Ge, Shundi; Kohn, Lisa A.; Jang, Julie K.; Andrade, Jacob; Wang, Xiaoyan

doi:10.1016/j.bbmt.2012.01.006

Cited by 12 publications

(14 citation statements)

References 25 publications

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“…Although the role of ECs during tissue regeneration has traditionally been attributed to their role in vascularization, including in the thymus (25), recent work has suggested that ECs can also contribute towards regeneration via their production of so-called angiocrine factors (26–28). Using a technique to constitutively activate the Akt pathway in ECs using the prosurvival adenoviral gene E4ORF1 (29), ECs can be propagated and expanded ex vivo (exEC) while maintaining their phenotype and vascular tube formation capacity (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration

et al. 2018

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The thymus is extremely sensitive to damage but also has a remarkable ability to repair itself. However, the mechanisms underlying this endogenous regeneration remain poorly understood and this capacity diminishes considerably with age. Here we show that thymic endothelial cells (ECs) comprise a critical pathway of regeneration, via their production of BMP4. ECs increased their production of BMP4 after thymic damage, and abrogating BMP4 signalling or production by either pharmacologic or genetic inhibition impaired thymic repair. EC-derived BMP4 acted on thymic epithelial cells (TECs) to increase their expression of Foxn1, a key transcription factor involved in TEC development, maintenance and regeneration; and its downstream targets such as Dll4, itself a key mediator of thymocyte development and regeneration. These studies demonstrate the importance of the BMP4 pathway in endogenous tissue regeneration and offer a potential clinical approach to enhance T cell immunity.

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Section: Resultsmentioning

confidence: 99%

Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration

et al. 2018

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“…These include IL-7, CXCL12, SCF, CCL25, and the notch ligand DLL4. In fact, many of these have been identified as part of the mechanistic pathways for exogenous thymic regeneration through such systemic means as sex steroid ablation, which crucially needs IL-7 (but not KGF) to mediate regeneration (76), and induces expression of the Notch ligand Dll4 (36), CCL25, which induces importation of progenitors (35), and VEGF, which promotes vascularization and endothelial cell function and is also likely involved in endogenous thymic regeneration (77, 78). …”

Section: Endogenous Thymic Regenerationmentioning

confidence: 99%

Thymus: the next (re)generation

Chaudhry

Velardi

Dudakov

et al. 2016

Immunological Reviews

141

131

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Summary As the primary site of T cell development, the thymus plays a key role in the generation of a strong yet self-tolerant adaptive immune response, essential in the face of the potential threat from pathogens or neoplasia. As the importance of the role of the thymus has grown, so too has the understanding that it is extremely sensitive to both acute and chronic injury. The thymus undergoes rapid degeneration following a range of toxic insults, and also involutes as part of the aging process, albeit at a faster rate than many other tissues. The thymus is, however, capable of regenerating, restoring its function to a degree. Potential mechanisms for this endogenous thymic regeneration include keratinocyte growth factor (KGF) signaling, and a more recently described pathway in which innate lymphoid cells produce interleukin-22 (IL-22) in response to loss of double positive thymocytes and upregulation of IL-23 by dendritic cells. Endogenous repair is unable to fully restore the thymus, particularly in the aged population, and this paves the way towards the need for exogenous strategies to help regenerate or even replace thymic function. Therapies currently in clinical trials include KGF, use of the cytokines IL-7 and IL-22, and hormonal modulation including growth hormone administration and sex steroid inhibition. Further novel strategies are emerging in the pre-clinical setting, including the use of precursor T cells and thymus bioengineering. The use of such strategies offers hope that for many patients, the next regeneration of their thymus is a step closer.

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“…We have tested to determine whether in vitro-derived progenitors are capable of thymus settling in adult mice, and we observed a low frequency of mice with thymus engraftment (data not shown). The precise reasons for the difference in engraftment between the neonatal and the adult is unknown, however, the increase in the neonatal vasculature compared with adults, 43 severe thymus involution and continued atrophy in adult NSG mice may be factors influencing human proT-cell engraftment in neonatal vs adult mice.…”

Section: Blood 19 December 2013 X Volume 122 Number 26 In Vitro Promentioning

confidence: 99%

Human proT-cells generated in vitro facilitate hematopoietic stem cell-derived T-lymphopoiesis in vivo and restore thymic architecture

Awong

Singh

Mohtashami

et al. 2013

Blood

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• Intrathymic T-cell regeneration is facilitated by human proTcells generated in vitro.• In vitro-generated human proT-cells home to the thymus, wherein they restore thymic structure.Hematopoietic stem cell transplantation (HSCT) is followed by a period of immune deficiency due to a paucity in T-cell reconstitution. Underlying causes are a severely dysfunctional thymus and an impaired production of thymus-seeding progenitors in the host. Here, we addressed whether in vitro-derived human progenitor T (proT)-cells could not only represent a source of thymus-seeding progenitors, but also able to influence the recovery of the thymic microenvironment. We examined whether co-transplantation of in vitro-derived human proT-cells with hematopoietic stem cells (HSCs) was able to facilitate HSC-derived T-lymphopoiesis posttransplant. A competitive transfer approach was used to define the optimal proT subset capable of reconstituting immunodeficient mice. Although the 2 subsets tested (proT1,1 ) showed thymus engrafting function, proT2-cells exhibited superior engrafting capacity. Based on this, when proT2-cells were coinjected with HSCs, a significantly improved and accelerated HSC-derived T-lymphopoiesis was observed. Furthermore, we uncovered a potential mechanism by which receptor activator of nuclear factor kb (RANK) ligand-expressing proT2-cells induce changes in both the function and architecture of the thymus microenvironment, which favors the recruitment of bone marrow-derived lymphoid progenitors. Our findings provide further support for the use of Notch-expanded progenitors in cellbased therapies to aid in the recovery of T-cells in patients undergoing HSCT. (Blood. 2013;122(26):4210-4219)

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Rapid Thymic Reconstitution Following Bone Marrow Transplantation in Neonatal Mice is VEGF-Dependent

Cited by 12 publications

References 25 publications

Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration

Production of BMP4 by endothelial cells is crucial for endogenous thymic regeneration

Thymus: the next (re)generation

Human proT-cells generated in vitro facilitate hematopoietic stem cell-derived T-lymphopoiesis in vivo and restore thymic architecture

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