TY - JOUR
T1 - Thymic rejuvenation via FOXN1reprogrammed embryonic fibroblasts (FREFs) to counteract age-related inflammation
AU - Oh, Jiyoung
AU - Wang, Weikan
AU - Thomas, Rachel
AU - Su, Dong Ming
N1 - Funding Information:
This work was supported by NIH/National Institute of Allergy and Infectious Diseases grant R01AI121147 to DMS. The funder had no role in study design, data collection, data analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
Copyright: © 2020, Oh et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2020/8
Y1 - 2020/8
N2 - Age-associated systemic, chronic inflammation is partially attributed to increased self-autoreactivity, resulting from disruption of central tolerance in the aged, involuted thymus. This involution causally results from gradually decreased expression of the transcription factor FOXN1 in thymic epithelial cells (TECs), whereas exogenous FOXN1 in TECs can partially rescue age-related thymic involution. TECs induced from FOXN1-overexpressing embryonic fibroblasts can generate an ectopic de novo thymus under the kidney capsule, and intrathymic injection of naturally young TECs can lead to middle-aged thymus regrowth. Therefore, as a thymic rejuvenation strategy, we extended these 2 findings by combining them with 2 types of promoter-driven (Rosa26CreERT and FoxN1Cre) Cre-mediated FOXN1-reprogrammed embryonic fibroblasts (FREFs). We engrafted these FREFs directly into the aged murine thymus. We found substantial regrowth of the native aged thymus with rejuvenated architecture and function in both males and females, exhibiting increased thymopoiesis and reinforced thymocyte negative selection, along with reduced senescent T cells and autoreactive T cell-mediated inflammation in old mice. Therefore, this approach has preclinical significance and presents a strategy to potentially rescue decreased thymopoiesis and perturbed negative selection to substantially, albeit partially, restore defective central tolerance and reduce subclinical autoimmune symptoms in elderly people.
AB - Age-associated systemic, chronic inflammation is partially attributed to increased self-autoreactivity, resulting from disruption of central tolerance in the aged, involuted thymus. This involution causally results from gradually decreased expression of the transcription factor FOXN1 in thymic epithelial cells (TECs), whereas exogenous FOXN1 in TECs can partially rescue age-related thymic involution. TECs induced from FOXN1-overexpressing embryonic fibroblasts can generate an ectopic de novo thymus under the kidney capsule, and intrathymic injection of naturally young TECs can lead to middle-aged thymus regrowth. Therefore, as a thymic rejuvenation strategy, we extended these 2 findings by combining them with 2 types of promoter-driven (Rosa26CreERT and FoxN1Cre) Cre-mediated FOXN1-reprogrammed embryonic fibroblasts (FREFs). We engrafted these FREFs directly into the aged murine thymus. We found substantial regrowth of the native aged thymus with rejuvenated architecture and function in both males and females, exhibiting increased thymopoiesis and reinforced thymocyte negative selection, along with reduced senescent T cells and autoreactive T cell-mediated inflammation in old mice. Therefore, this approach has preclinical significance and presents a strategy to potentially rescue decreased thymopoiesis and perturbed negative selection to substantially, albeit partially, restore defective central tolerance and reduce subclinical autoimmune symptoms in elderly people.
UR - http://www.scopus.com/inward/record.url?scp=85091191956&partnerID=8YFLogxK
U2 - 10.1172/JCI.INSIGHT.140313
DO - 10.1172/JCI.INSIGHT.140313
M3 - Article
C2 - 32790650
AN - SCOPUS:85091191956
SN - 2379-3708
VL - 5
JO - JCI Insight
JF - JCI Insight
IS - 18
M1 - e140313
ER -