Enhancing T Lineage Production in Aged Mice: A Novel Function of Foxn1 in the Bone Marrow Niche

Abstract

Foxn1 is essential for thymic organogenesis and T lymphopoiesis. While reduced Foxn1 expression results in a decline in T lymphopoiesis, overexpression of Foxn1 in the thymus of a transgenic mouse model (Foxn1Tg) attenuates the age-associated decline in T lymphopoiesis. T lymphopoiesis begins with ETP, derived from MPP in the BM. A decline in MPP and ETP numbers with age is thought to contribute to reduced T lymphopoiesis. Previously, we showed that reduced ETP number with age is attenuated in Foxn1Tg; whether the effect is initiated in the BM with MPP is not known. Here, we report that Foxn1 is expressed in Wt BM and over-expressed in Foxn1Tg. With age, the number of MPP in Foxn1Tg was not reduced, and Foxn1Tg also have a larger pool of HSC. Furthermore, the Foxn1Tg BM is more efficient in generating MPP. In contrast to MPP, CLP and B lineage cell numbers were significantly lower in both young and aged Foxn1Tg compared to Wt. We identified a novel population of lineageneg/low, CD45pos EpCAMpos, SCA1pos, CD117neg, CD138neg, MHCIIneg cells as Foxn1-expressing BM cells that also express Delta-like 4. Thus, Foxn1 affects both T lymphopoiesis and hematopoiesis, and the Foxn1 BM niche may function in skewing MPP development toward T lineage progenitors.

Role of Bone Marrow Maturity, Insulin-Like Growth Factor 1 Receptor, and Forkhead Box Protein N1 in Thymic Involution and Rejuvenation

“…Functional maturation of TECs requires expression of FOXN1, which may also play a role in the cross‐talk between TECs and the developing thymocytes . In addition, it has been shown that FOXN1 is expressed on BM cells as well as BM‐derived TECs . The expression of FOXN1 in BM cells does not change with age; however, it does play an important role in the maintenance of T cell lineage through the development of T cell progenitor cells .…”

Biological significance of FoxN1 gain-of-function mutations during T and B lymphopoiesis in juvenile mice

“… 4 , 8 , 9 , 10 , 11 , 38 , 39 However, the biological significance of inborn and postnatal FoxN1 gain-of-function mutations has just begun to be probed. 12 , 14 , 15 , 20 , 24 In this report, we used our newly developed inducible tissue-specific mouse model for FoxN1 gain-of-function mutations to establish biologically significant evidence that over- and ectopic-expression of FoxN1 in early life influences immature TEC, T and B cell, and skin epithelial development. We found that K14Cre-mediated Rosa26-STOP flox – FoxN1 Tg newborns had a neonatal lethal phenotype caused by dehydration due to abnormal permeability in the skin and defect in nursing.…”

“…This is consistent with the finding in K14 promoter-driven FoxN1 transgenic mice, in which B-lineage cell numbers were significantly lower. 20 It could be caused by exogenous FoxN1 expression in nonprominent locations, not only in BM mesenchymal origin stromal cells but also in hematopoietic origin cells because of ubiquitous CreER T .…”

“…In addition, another recent report using the same K14-FoxN1 transgenic mice showed that FoxN1 expressed in the bone marrow (BM) of K14 + stroma, which is not a prominent site of FoxN1 expression, promoted T-lineage production, but inhibited B-lineage production. 20 Therefore, another question about the role of FoxN1 in nonprominent locations arises.…”

IL22 Regulates Human Urothelial Cell Sensory and Innate Functions through Modulation of the Acetylcholine Response, Immunoregulatory Cytokines and Antimicrobial Peptides: Assessment of an In Vitro Model

“…Isolated RNA was then treated with DNase using Ambion DNA-free kit and 0.5–2 µg of RNA was used for cDNA synthesis using the Invitrogen’s SuperScript II synthesis kit. Quantitative RT-PCR was performed on an Applied Biosystems 7100 as we have previously described [45] . Sequences for the primers are presented in Table 3 ; all are selected using Primer Express software (Aplied Biosystems).…”