From: Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies
 | Preclinical model | Evidence |
---|---|---|
Activated Hh signaling | • Ptch mutant chimeric explant cultures | • Hh signaling from ventral tissues surrounding the AGM was shown to induce and increase HSC activity in a time-dependent manner[64] |
• Ptch+/− mice vs wild-type mice (bone marrow, fetal liver cells) | • Hh signaling enhanced regeneration potential in short-term HSCs through increased HSC number[66], enhanced recoverability following 5-FU treatment[65, 66], and increased regeneration capacity[65, 66] | |
• In long-term HSCs with activated Hh signaling, repopulating cells were eventually exhausted in the bone marrow[66], whereas fetal liver cells showed long-term regeneration capacity[65] | ||
• Conditional loss of Ptch in adult murine HSCs | • Ptch deletion in HSCs did not cause Hh pathway activation or affect hematopoiesis[67] | |
• Conditional loss of Ptch in adult murine non-HSCs | ||
• Ptch deletion in non-HSCs led to aberrant hematopoiesis, including apoptosis of lymphoid progenitors in epithelial cells, increased numbers of lineage-negative bone marrow cells, and increased mobilization of myeloid progenitors in bone marrow niche cells[67] | ||
Impaired Hh signaling | • Ihh−/− knockout mice | • Terminal erythroid differentiation was defective despite normal production of HSCs and progenitor cells[62] |
• Dhh- deficient mouse model | • Dhh was shown to regulate normal and stress-induced erythropoiesis by preventing erythropoiesis differentiation in the spleen and bone marrow[71] | |
• Conditional deletion of Smo in fetal and adult hematopoietic and endothelial cells (Vav driven Cre-Lox system) | • Decreased stem cell activity was observed despite normal number and differentiation of HSCs[68] | |
• Smo- depleted mouse stromal cells | • Differentiation of hematopoietic progenitors was impaired—the number of myeloid progenitors was increased at the expense of lymphoid progenitors[72] | |
• Caused reduced expression of factors involved in B-cell development or osteoblast differentiation | ||
• Gli1null mice | • Decreased proliferation of long-term HSCs and myeloid progenitors, reduced myeloid differentiation, and delayed recovery following 5-FU treatment were observed[69] | |
 | • Human pluripotent stem cells | • Gli3R, the repressor form of Gli3, was shown to be necessary and sufficient in the initiation and regulation of adult hematopoietic specification[70] |