Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY, USA.
Blood. 2011 Sep 1;118(9):2420-9. doi: 10.1182/blood-2010-09-305664. Epub 2011 Jun 7.
The role of Wnt signaling in hematopoietic stem cell fate decisions remains controversial. We elected to dysregulate Wnt signaling from the perspective of the stem cell niche by expressing the pan Wnt inhibitor, Wnt inhibitory factor 1 (Wif1), specifically in osteoblasts. Here we report that osteoblastic Wif1 overexpression disrupts stem cell quiescence, leading to a loss of self-renewal potential. Primitive stem and progenitor populations were more proliferative and elevated in bone marrow and spleen, manifesting an impaired ability to maintain a self-renewing stem cell pool. Exhaustion of the stem cell pool was apparent only in the context of systemic stress by chemotherapy or transplantation of wild-type stem cells into irradiated Wif1 hosts. Paradoxically this is mediated, at least in part, by an autocrine induction of canonical Wnt signaling in stem cells on sequestration of Wnts in the environment. Additional signaling pathways are dysregulated in this model, primarily activated Sonic Hedgehog signaling in stem cells as a result of Wif1-induced osteoblastic expression of Sonic Hedgehog. We find that dysregulation of the stem cell niche by overexpression of an individual component impacts other unanticipated regulatory pathways in a combinatorial manner, ultimately disrupting niche mediated stem cell fate decisions.
Wnt 信号在造血干细胞命运决定中的作用仍然存在争议。我们选择从干细胞龛的角度失调 Wnt 信号，通过在成骨细胞中特异性表达泛 Wnt 抑制剂 Wnt 抑制因子 1（Wif1）来实现。在这里，我们报告成骨细胞中 Wif1 的过表达破坏了干细胞静止状态，导致自我更新潜能丧失。原始干细胞和祖细胞群体在骨髓和脾脏中增殖增加，表现出维持自我更新干细胞池的能力受损。只有在化疗或野生型干细胞移植到辐射 Wif1 宿主引起的全身应激情况下，才会明显耗尽干细胞池。矛盾的是，这种情况至少部分是通过环境中 Wnts 的隔离引起干细胞中经典 Wnt 信号的自分泌诱导介导的。在这个模型中，其他信号通路也失调，主要是由于 Wif1 诱导的 Sonic Hedgehog 信号在干细胞中的表达，导致 Sonic Hedgehog 信号的激活。我们发现，通过过表达单个成分失调干细胞龛会以组合方式影响其他未预料到的调节途径，最终破坏龛介导的干细胞命运决定。
