Veneto Institute of Molecular Medicine, Padova, Italy.
Department of Medicine, University of Padova, Padova, Italy.
Diabetes. 2020 Jul;69(7):1562-1572. doi: 10.2337/db19-0640. Epub 2020 Apr 28.
Mobilization of hematopoietic stem/progenitor cells (HSPC) from the bone marrow (BM) is impaired in diabetes. Excess oncostatin M (OSM) produced by M1 macrophages in the diabetic BM signals through p66Shc to induce in stromal cells and retain HSPC. BM adipocytes are another source of CXCL12 that blunts mobilization. We tested a strategy of pharmacologic macrophage reprogramming to rescue HSPC mobilization. In vitro, PPAR-γ activation with pioglitazone switched macrophages from M1 to M2, reduced expression, and prevented transcellular induction of In diabetic mice, pioglitazone treatment downregulated , , and in the hematopoietic BM, restored the effects of granulocyte-colony stimulation factor (G-CSF), and partially rescued HSPC mobilization, but it increased BM adipocytes. deletion recapitulated the effects of pioglitazone on adipogenesis, which was p66Shc independent, and double knockout of Osm and p66Shc completely rescued HSPC mobilization. In the absence of OSM, BM adipocytes produced less CXCL12, being arguably devoid of HSPC-retaining activity, whereas pioglitazone failed to downregulate in BM adipocytes. In patients with diabetes on pioglitazone therapy, HSPC mobilization after G-CSF was partially rescued. In summary, pioglitazone reprogrammed BM macrophages and suppressed OSM signaling, but sustained expression by BM adipocytes could limit full recovery of HSPC mobilization.
造血干细胞/祖细胞（HSPC）从骨髓（BM）中的动员在糖尿病中受损。糖尿病 BM 中 M1 巨噬细胞产生的过量肿瘤坏死因子样细胞因子 11（OSM）通过 p66Shc 信号转导诱导基质细胞中的 并保留 HSPC。骨髓脂肪细胞是另一种 CXCL12 来源，其削弱了动员。我们测试了一种药理学巨噬细胞重编程策略以挽救 HSPC 动员。在体外，用吡格列酮激活过氧化物酶体增殖物激活受体-γ（PPAR-γ）将巨噬细胞从 M1 型切换为 M2 型，降低了 表达，并防止了 CXCL12 跨细胞诱导。在糖尿病小鼠中，吡格列酮治疗下调了 、 和 在造血 BM 中的表达，恢复了粒细胞集落刺激因子（G-CSF）的作用，并部分挽救了 HSPC 动员，但增加了 BM 脂肪细胞。 缺失再现了吡格列酮对脂肪生成的作用，该作用不依赖于 p66Shc，而 Osm 和 p66Shc 的双重缺失则完全挽救了 HSPC 动员。在没有 OSM 的情况下，BM 脂肪细胞产生的 CXCL12 较少，几乎没有保留 HSPC 的活性，而吡格列酮未能下调 BM 脂肪细胞中的 。在接受吡格列酮治疗的糖尿病患者中，G-CSF 后 HSPC 动员得到部分挽救。总之，吡格列酮重编程 BM 巨噬细胞并抑制 OSM 信号，但 BM 脂肪细胞中持续的 表达可能限制 HSPC 动员的完全恢复。
