Department of Biological Sciences, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
Research Institute of Women's Health, Sookmyung Women's University, Seoul, 04310, Republic of Korea.
Cell Commun Signal. 2023 Jun 27;21(1):158. doi: 10.1186/s12964-023-01143-y.
Bone marrow (BM) is progressively filled with adipocytes during aging process. Thus, BM adipocytes-derived adiponectin (APN) affects the function of bone marrow-derived mesenchymal stem cells (BMSCs). However, little is known about the effect of APN on migration ability of BMSCs cultured under hypoxic conditions, which is similar to the BM microenvironment.
We found that the population and migration ability of BMSCs from APN KO mice was higher than that of WT mice due to increased stability of hypoxia inducible factor 1α (HIF1α). Stem cell factor (SCF)-activated STAT3 stimulated the induction of HIF1α which further stimulated SCF production, indicating that the SCF/STAT3/HIF1α positive loop was highly activated in the absence of APN. It implies that APN negatively regulated this positive loop by stimulating HIF1α degradation via the inactivation of GSK3β. Furthermore, APN KO BMSCs were highly migratory toward EL-4 lymphoma, and the interaction between CD44 in BMSCs and hyaluronic acid (HA) from EL-4 enhanced the migration of BMSCs. On the other hand, the migrated BMSCs recruited CD8 T cells into the EL-4 tumor tissue, resulting in the retardation of tumor growth. Additionally, gradually increased APN in BM on the aging process affects migration and related functions of BMSCs, thus aged APN KO mice showed more significant suppression of EL-4 growth than young APN KO mice due to higher migration and recruitment of CD8 T cells.
APN deficiency enhances CD44-mediated migration ability of BMSCs in the hypoxic conditions by the SCF/STAT3/HIF1α positive loop and influences the migration ability of BMSCs for a longer time depending on the aging process. Video Abstract.
骨髓（BM）在衰老过程中逐渐充满脂肪细胞。因此，骨髓脂肪细胞衍生的脂联素（APN）影响骨髓来源间充质干细胞（BMSCs）的功能。然而，对于 APN 对低氧条件下培养的 BMSCs 迁移能力的影响知之甚少，这种条件类似于 BM 微环境。
我们发现 APN 基因敲除（KO）小鼠的 BMSCs 群体和迁移能力高于 WT 小鼠，这是由于缺氧诱导因子 1α（HIF1α）的稳定性增加。干细胞因子（SCF）激活的 STAT3 刺激 HIF1α 的诱导，进而刺激 SCF 的产生，表明在没有 APN 的情况下，SCF/STAT3/HIF1α 正反馈环路高度激活。这意味着 APN 通过刺激 HIF1α 降解来负调控这个正反馈环，从而使 GSK3β失活。此外，APN KO BMSCs 对 EL-4 淋巴瘤具有高度迁移性，并且 BMSCs 中的 CD44 与 EL-4 中的透明质酸（HA）之间的相互作用增强了 BMSCs 的迁移性。另一方面，迁移的 BMSCs 将 CD8 T 细胞募集到 EL-4 肿瘤组织中，导致肿瘤生长减缓。此外，随着衰老过程中 BM 中 APN 的逐渐增加，会影响 BMSCs 的迁移和相关功能，因此，与年轻的 APN KO 小鼠相比，年老的 APN KO 小鼠对 EL-4 生长的抑制作用更为明显，这是由于 CD8 T 细胞的迁移和募集增加所致。
APN 缺乏通过 SCF/STAT3/HIF1α 正反馈环增强 BMSCs 在低氧条件下的 CD44 介导的迁移能力，并随着衰老过程的进行，对 BMSCs 的迁移能力产生更长时间的影响。
