Program in Biochemistry, The Graduate Center of the City University of New York, New York, NY 10016, USA.
Department of Biology, City College of New York CUNY, New York, NY 10031, USA.
J Immunol Res. 2022 Apr 29;2022:6061746. doi: 10.1155/2022/6061746. eCollection 2022.
In paradox to critical functions for T-cell selection and self-tolerance, the thymus undergoes profound age-associated atrophy and loss of T-cell function, further enhanced by cancer therapies. Identifying thymic epithelial progenitor populations capable of forming functional thymic tissue will be critical in understanding thymic epithelial cell (TEC) ontogeny and designing strategies to reverse involution. We identified a new population of progenitor cells, present in both the thymus and bone marrow (BM) of mice, that coexpress the hematopoietic marker CD45 and the definitive thymic epithelial marker EpCAM and maintain the capacity to form functional thymic tissue. Confocal analysis and qRT-PCR of sorted cells from both BM and thymus confirmed coexpression of CD45 and EpCAM. Grafting of C57BL/6 fetal thymi under the kidney capsule of H2BGFP transgenic mice revealed that peripheral CD45+ EpCAM+ GFP-expressing cells migrate into the developing thymus and contribute to both TECs and FSP1-expressing thymic stroma. Sorted BM-derived CD45+ EpCAM+ cells contribute to reaggregate thymic organ cultures (RTOCs) and differentiate into keratin and FoxN1-expressing TECs, demonstrating that BM cells can contribute to the maintenance of TEC microenvironments previously thought to be derived solely from endoderm. BM-derived CD45+ EpCAM+ cells represent a new source of progenitor cells that contribute to thymic homeostasis. Future studies will characterize the contribution of BM-derived CD45+ EpCAM+ TEC progenitors to distinct functional TEC microenvironments in both the steady-state thymus and under conditions of demand. Cell therapies utilizing this population may help counteract thymic involution in cancer patients.
与 T 细胞选择和自身耐受的关键功能相反，胸腺会发生深刻的与年龄相关的萎缩和 T 细胞功能丧失，而癌症治疗进一步加剧了这种情况。鉴定能够形成功能性胸腺组织的胸腺上皮祖细胞群体对于理解胸腺上皮细胞（TEC）发生和设计逆转退化的策略将是至关重要的。我们鉴定了一种新的祖细胞群体，存在于小鼠的胸腺和骨髓（BM）中，这些细胞共同表达造血标志物 CD45 和确定性胸腺上皮标志物 EpCAM，并保持形成功能性胸腺组织的能力。对来自 BM 和胸腺的分选细胞进行共聚焦分析和 qRT-PCR 证实了 CD45 和 EpCAM 的共表达。将 H2BGFP 转基因小鼠的肾脏包膜下的 C57BL/6 胎胸腺移植，揭示了外周血 CD45+EpCAM+GFP 表达细胞迁移到正在发育的胸腺中，并有助于 TEC 和 FSP1 表达的胸腺基质。分选的 BM 来源的 CD45+EpCAM+细胞有助于再聚集胸腺器官培养物（RTOCs），并分化为角蛋白和 FoxN1 表达的 TEC，表明 BM 细胞可以有助于维持先前认为仅源自内胚层的 TEC 微环境。BM 来源的 CD45+EpCAM+细胞代表了一种新的祖细胞来源，有助于胸腺的稳态。未来的研究将表征 BM 来源的 CD45+EpCAM+TEC 祖细胞对稳定状态胸腺和需求条件下不同功能 TEC 微环境的贡献。利用该群体的细胞治疗可能有助于对抗癌症患者的胸腺退化。
