Table 1 Preclinical evidence for Hh pathway involvement in hematopoiesis and in progenitor expansion and maintenance

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

• Gli1^null 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

• Gli3^R, the repressor form of Gli3, was shown to be necessary and sufficient in the initiation and regulation of adult hematopoietic specification[70]