Gli1 regulates the proliferation and differentiation of HSCs and myeloid progenitors

The Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Blood (Impact Factor: 10.45). 03/2010; 115(12):2391-6. DOI: 10.1182/blood-2009-09-241703
Source: PubMed


The Hedgehog (Hh) pathway is essential for normal embryonic development and tissue repair. The role of Hh signaling in hematopoiesis has been studied primarily by modulating the activity of Patched and Smoothened, but results have been conflicting. Some studies demonstrate a requirement for pathway activity in hematopoiesis, whereas others report that it is dispensable. Hh activity converges on the Gli transcription factors, but the specific role of these downstream effectors in hematopoiesis has not been reported. We have analyzed hematopoietic stem cell (HSC) and progenitor function in mice with a homozygous deletion of Gli1 (Gli1(null)). Gli1(null) mice have more long-term HSCs that are more quiescent and show increased engraftment after transplantation. In contrast, myeloid development is adversely affected with decreased in vitro colony formation, decreased in vivo response to granulocyte colony-stimulating factor (G-CSF), and impaired leukocyte recovery after chemotherapy. Levels of the proto-oncogene Cyclin D1 are reduced in Gli1(null) mice and may explain the loss of proliferation seen in HSCs and progenitor cells. These data demonstrate that Gli1 regulates normal and stress hematopoiesis. Moreover, they suggest that Gli1 and Smoothened may not be functionally redundant, and direct GLI1 inhibitors may be needed to effectively block HH/GLI1 activity in human disease.

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    • "Activated Hh signaling through loss of Ptch leads to increased HSC formation and activity [64,66], enhanced recoverability following treatment with 5-fluorouracil [65,66], and increased regeneration capacity [65,66]. Conversely, loss of pathway activity through mutation of the downstream effector, Gli1, in mice leads to decreased proliferation of long-term HSCs and myeloid progenitors, reduced myeloid differentiation, and delayed recovery following 5-fluorouracil treatment [69]. Interestingly, reduced HSC activity (through loss of Gli1) led to increased engraftment. "
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    • "For example, leukemia stem cell maintenance and expansion are dependent on Hh signaling.138,175 The effect of Hh signaling on a normal hematopoietic stem cell population, however, is still quite controversial, with some showing effects but others with no effects.138,177–180 Based on cancer stem cell theory, it is anticipated that Hh signaling activation exerts resistance to cancer chemotherapy and radiotherapy.181 "
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    • "Since Hh signaling has been linked to a variety of cancers, some of which develop in the setting of inflammation [29], [30], [31], we examined the role of Gli1, a known component of the Hh signaling pathway, in the transition from chronic inflammation to mucous neck cell metaplasia or SPEM. Gli1 is expressed in both intestinal myeloid and myofibroblasts [11], consistent with prior studies showing Gli1 in hematopoietic stem cells [32], [33]. We can only speculate as to why Gli1 is lost only in α-SMA+ cells of the muscularis mucosa in response to H. felis, but not in the intraglandular mesenchyme. "
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