Walkley Carl R, Shea Jeremy M, Sims Natalie A, Purton Louise E, Orkin Stuart H
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology and Stem Cell Program, Children's Hospital Boston, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2007 Jun 15;129(6):1081-95. doi: 10.1016/j.cell.2007.03.055.
Hematopoiesis is maintained by stem cells (HSCs) that undergo fate decisions by integrating intrinsic and extrinsic signals, with the latter derived from the bone marrow (BM) microenvironment. Cell-cycle regulation can modulate stem cell fate, but it is unknown whether this represents an intrinsic or extrinsic effector of fate decisions. We have investigated the role of the retinoblastoma protein (RB), a central regulator of the cell cycle, in hematopoiesis. Widespread inactivation of RB in the murine hematopoietic system resulted in profound myeloproliferation. HSCs were lost from the BM due to mobilization to extramedullary sites and differentiation. This phenotype was not intrinsic to HSCs, but, rather, was the consequence of an RB-dependent interaction between myeloid-derived cells and the microenvironment. These findings demonstrate that myeloproliferation may result from perturbed interactions between hematopoietic cells and the niche. Therefore, RB extrinsically regulates HSCs by maintaining the capacity of the BM to support normal hematopoiesis and HSCs.
造血作用由干细胞（HSCs）维持，这些干细胞通过整合内在和外在信号来进行命运抉择，后者源自骨髓（BM）微环境。细胞周期调控能够调节干细胞命运，但尚不清楚这是命运决定的内在还是外在效应器。我们研究了细胞周期的核心调节因子视网膜母细胞瘤蛋白（RB）在造血作用中的作用。小鼠造血系统中RB的广泛失活导致了严重的骨髓增殖。造血干细胞因迁移至髓外部位并分化而从骨髓中丢失。这种表型并非造血干细胞所固有，而是髓系来源细胞与微环境之间RB依赖性相互作用的结果。这些发现表明，骨髓增殖可能是造血细胞与微环境之间相互作用紊乱所致。因此，RB通过维持骨髓支持正常造血和造血干细胞的能力，从外部调节造血干细胞。
