Larsson Jonas, Blank Ulrika, Klintman Jenny, Magnusson Mattias, Karlsson Stefan
Department of Molecular Medicine and Gene Therapy, Institute of Laboratory Medicine, Lund University Hospital, Lund, Sweden.
Exp Hematol. 2005 May;33(5):592-6. doi: 10.1016/j.exphem.2005.02.003.
Maintained quiescence of hematopoietic stem cells (HSCs) is of critical importance to prevent premature exhaustion of the stem cell pool under conditions of hematopoietic stress. The growth inhibitory cytokine transforming growth factor beta (TGF-beta) has been shown to play a critical role in maintaining quiescence of HSCs in vitro. Here, we have used conditional knockout mice for the TGF-beta type I receptor (TbetaRI) to ask whether the naturally quiescent state of HSCs in vivo is dependent on TGF-beta signaling and thus whether TGF-beta serves as a protective factor for the stem cell pool during conditions of stress.
TbetaRI null and control bone marrow chimeras were subjected to repeated treatments with the cell cycle-specific cytotoxic drug 5-fluorouracil (5-FU) and surviving HSCs were assayed by competitive transplantation experiments. Exhaustion of stem cells was provoked by serially transplanting TGF-beta signaling-deficient as well as normal BM cells into lethally irradiated recipients, which were monitored for survival.
Surprisingly, we found that TGF-beta receptor-deficient HSCs have similar susceptibility, compared to controls, to repeated 5-FU treatments, indicative of normally maintained quiescence in these cells. Likewise, hematopoietic failure occurred at similar stages in serially transplanted recipients of TbetaRI null and control BM, respectively, demonstrating normal consumption of the stem cell pool during hematopoietic stress.
These findings clearly demonstrate that, despite a key role in vitro, TGF-beta does not provide the necessary signal that induces the quiescent state of HSCs and maintains the stem cell pool in vivo.
维持造血干细胞（HSC）的静止状态对于防止在造血应激条件下干细胞池过早耗竭至关重要。生长抑制细胞因子转化生长因子β（TGF-β）已被证明在体外维持HSC的静止状态中起关键作用。在此，我们使用TGF-βI型受体（TβRI）条件性敲除小鼠来探究体内HSC的天然静止状态是否依赖于TGF-β信号传导，以及在应激条件下TGF-β是否作为干细胞池的保护因子。
TβRI基因敲除和对照骨髓嵌合体接受细胞周期特异性细胞毒性药物5-氟尿嘧啶（5-FU）的重复治疗，并通过竞争性移植实验检测存活的HSC。通过将TGF-β信号缺陷型以及正常骨髓细胞连续移植到致死性照射的受体中引发干细胞耗竭，并监测受体的存活情况。
令人惊讶的是，我们发现与对照相比，TGF-β受体缺陷型HSC对重复的5-FU治疗具有相似的敏感性，表明这些细胞中静止状态正常维持。同样，在TβRI基因敲除和对照骨髓的连续移植受体中，造血衰竭分别发生在相似阶段，表明在造血应激期间干细胞池的正常消耗。
这些发现清楚地表明，尽管TGF-β在体外起关键作用，但它并不能提供诱导HSC静止状态并在体内维持干细胞池的必要信号。
