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Twisting the bone marrow stem cell niche
Haixia Niu1 and Jose A. Cancelas1,2
1Division of Experimental Hematology and Cancer Biology, Cancer & Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., Cincinnati, and 2Hoxworth Blood Center, University of Cincinnati Academic Health Center, OH, USA
E-mail: jose.cancelas@uc.edu doi:10.3324/haematol.2018.206029
Hematopoietic stem cells (HSC) are the source of blood cells over the whole lifespan of mammals. HSC locate in the bone marrow microenvironment in the so-called bone marrow stem cell niche. This niche consists of multiple cell types, such as endothelial cells, mesenchymal stem cells (MSC), CXCL12-expressing adventitial cells (CAR cells), non- myelinating Schwann cells, pericytes, osteoblasts, adipocytes and hematopoietic cells including osteoclasts, regulatory T cells, macrophages and neutrophils.1 Our understanding of the specific contributions of each of these populations derives from the use of constitutional or inducible genetic murine models in which more-or-less specific niche cell populations are targeted for deletion, or for the introduction of loss-of-func- tion or gain-of-function mutations. However, the complicated but precise crosstalk between HSC and specific bone marrow HSC niche cells is still poorly understood. In this issue of the journal, Liu et al. report on their discovery that inducible defi- ciency of Twist1 in the bone marrow HSC niche results in a broad alteration of multiple niche cell types as well as a reduced production of major HSC supportive factors. The dys- regulated Twist1-deficient mesenchymal bone marrow HSC niche reduces HSC homing and retention, impairs HSC self- renewal and induces myeloid-biased differentiation. Furthermore, Twist1 deficiency in the bone marrow HSC niche accelerates the progression of MLL-AF9-induced acute myeloid leukemia (AML), partially through upregulated Jagged2/Notch signaling.2
Three significant aspects of this study need to be highlight- ed. First of all, the discovery adds new mechanisms to our understanding of how the bone marrow HSC niche regulates HSC function. Secondly, the findings provide cumulative evi- dence that remodeling of the bone marrow HSC niche plays an important role in leukemogenesis and is, therefore, a potential drug target for therapy. Last but not least, the authors identi- fied a new function of the transcription factor Twist1 which participates in normal and malignant hematopoiesis.
Niche Twist1 deficiency impairs hematopoietic stem cell function, homing and retention
Twist proteins are members of the basic Helix-Loop-Helix transcription factor family with highly conserved sequences. There are two Twist proteins, Twist1 and Twist2. They are well-known for their essential functions in development.3 In the hematopoietic system, Twist1 is expressed in HSC and progenitors, while Twist2 is expressed in more differentiated myeloid lineage cells. However, the function of Twist1 in hematopoiesis has not been well studied. Earlier studies by the same group demonstrated that Twist1 is a regulator of HSC self-renewal and lineage commitment.4 Twist1 also partici- pates in the regulation of MSC function and in MSC self- renewal. Twist1 overexpression in MSC increased C-X-C motif chemokine 12 ligand (Cxcl12) production, which enhanced the capacity to maintain human HSC and progeni-
tors in stromal-dependent long-term culture-initiating cell
assays. Twist1-deficient heterozygous mice showed reduced
5
numbers of MSC in the bone marrow. Twist1 also regulates
the cell fate and commitment of MSC. Twist1 silencing enhanced in vitro and in vivo osteogenic differentiation of human adipose-derived MSC by triggering the activation of BMP-ERK-FGF signaling and TAZ upregulation. Silencing Twist1 in a murine MSC cell line, C3H10T1/2, enhanced osteogenic differentiation.6 Using a chimeric mouse model, Liu et al., found that Twist1 deletion in the bone marrow niche leads to decreased numbers of MSC and mature osteoblasts,2 findings which are consistent with already reported data. However, both sinusoidal and arteriolar endothelial cell num- bers increased, consistent with an increase in the number of microvessels. This finding contrasts with that of earlier studies in which Twist1 upregulation, as identified in numerous carci- nomas, promoted neo-angiogenesis.7 These distinct roles of Twist1 in tumor epithelial cells may be attributed to the differ- ent microenvironment found in solid tumors compared with the bone marrow HSC niche. More studies need to be per- formed to address this difference.
Most HSC are retained in the BM niche in a quiescent state by interacting with the niche cells. The inducible deficiency of Twist1 in the bone marrow HSC niche promoted cell cycle entry of long-term HSC, impaired long-term HSC self-renewal and biased HSC differentiation to the myeloid lineage. The CXCL12-CXCR4 axis is essential for HSC retention in the bone marrow.8 Granulocyte-colony stimulating factor (G-CSF), an endogenously expressed cytokine secreted by MSC, osteo- lineage cells, endothelial cells and macrophages, induces mobi- lization of quiescent HSC through downregulation of bone marrow expression of CXCL12.9,10 Liu et al. found that the inducible deficiency of Twist1 impaired HSC homing and pro- moted HSC mobilization, effects associated with decreased expression of CXCL12 and other key cytokines/chemokines crucial for bone marrow HSC retention, such as VCAM, SCF, and Angpt1 in mutant bone marrow MSC, and increased G- CSF expression in bone marrow osteolineage cells and macrophages.2 Together with their earlier finding,4 these data indicate that Twist1 regulates HSC function in both a cell- autonomous and non-cell-autonomous manner.
An earlier study by the same group showed that Twist1 reg- ulates HSC myeloid differentiation by activating the myeloid transcription factors PU.1 and Gata1 and downregulating the lymphoid transcription factor Gata3.4 A Twist1-deficient bone marrow HSC niche promoted early myeloid differentiation.2 However, the underlying molecular mechanism was not iden- tified. Twist2, a homolog of Twist1, has also been identified as a major negative regulator of myeloid cell development and the pro-inflammatory responses of these cells.11 Twist2 is expressed in granulocyte-macrophage progenitors and inhibits their proliferation and differentiation into macrophages, neu- trophils and basophils through direct interactions and inhibi-
haematologica | 2018; 103(12)
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