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The suture provides a niche for mesenchymal stem cells of craniofacial bones.

Zhao H, Feng J, Ho TV, Grimes W, Urata M, Chai Y - Nat. Cell Biol. (2015)

Bottom Line: Gli1+ cells are typical MSCs in vitro.Ablation of Gli1+ cells leads to craniosynostosis and arrest of skull growth, indicating that these cells are an indispensable stem cell population.Twist1(+/-) mice with craniosynostosis show reduced Gli1+ MSCs in sutures, suggesting that craniosynostosis may result from diminished suture stem cells.

View Article: PubMed Central - PubMed

Affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103 Los Angeles, California 90033, USA.

ABSTRACT
Bone tissue undergoes constant turnover supported by stem cells. Recent studies showed that perivascular mesenchymal stem cells (MSCs) contribute to the turnover of long bones. Craniofacial bones are flat bones derived from a different embryonic origin than the long bones. The identity and regulating niche for craniofacial-bone MSCs remain unknown. Here, we identify Gli1+ cells within the suture mesenchyme as the main MSC population for craniofacial bones. They are not associated with vasculature, give rise to all craniofacial bones in the adult and are activated during injury repair. Gli1+ cells are typical MSCs in vitro. Ablation of Gli1+ cells leads to craniosynostosis and arrest of skull growth, indicating that these cells are an indispensable stem cell population. Twist1(+/-) mice with craniosynostosis show reduced Gli1+ MSCs in sutures, suggesting that craniosynostosis may result from diminished suture stem cells. Our study indicates that craniofacial sutures provide a unique niche for MSCs for craniofacial bone homeostasis and repair.

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IHH secreted from the osteogenic front signals to Gli1+ cells in the suture mesenchyme and regulates osteogenic lineage differentiation. (a) Immunohistochemical staining of CD31 (green) in the sagittal suture in Gli1-LacZ mice. CD31 labels vasculature. Dotted line outlines the parietal bone. (b) Suture mesenchyme in Shh-CreERT2;Tdtomatofl mice. One-month-old mice were induced and samples were collected two weeks later. (c,d) LacZ staining of the sagittal suture of Ihh-LacZ mice at 1 month of age. Ihh+ cells are detectable at the osteogenic front of the parietal bone (c) but not in the periosteum or dura (d). Dotted line outlines the parietal bone margin. (e,f) Immunohistochemical staining (red) of Sp7 (e) and Runx2 (f) in the suture mesenchyme of one-month-old Ihh-LacZ mice. Yellow indicates colocalization of fluorescent staining (arrows). (g-l) HE staining (g,h) and microCT analysis (i-l) of one-month-old Gli1-CreERT2;Smofl/fl and Gli1-CreERT2 (ctrl) mice after induction with tamoxifen. Samples were collected 8 months later. Boxed areas in g and h are displayed in the lower panels. MicroCT images in i and k are at the basosphenoid bone position. Arrows indicate basosphenoid bone; asterisks indicate patent sutures. MicroCT images in j and l are at the palatal bone position. Arrows indicate palatal bones; arrowheads indicate presphenoid bones; asterisks indicate patent sutures. Scale bars in panels i, j, k and l, 1mm; other scale bars, 100 μm.
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Figure 5: IHH secreted from the osteogenic front signals to Gli1+ cells in the suture mesenchyme and regulates osteogenic lineage differentiation. (a) Immunohistochemical staining of CD31 (green) in the sagittal suture in Gli1-LacZ mice. CD31 labels vasculature. Dotted line outlines the parietal bone. (b) Suture mesenchyme in Shh-CreERT2;Tdtomatofl mice. One-month-old mice were induced and samples were collected two weeks later. (c,d) LacZ staining of the sagittal suture of Ihh-LacZ mice at 1 month of age. Ihh+ cells are detectable at the osteogenic front of the parietal bone (c) but not in the periosteum or dura (d). Dotted line outlines the parietal bone margin. (e,f) Immunohistochemical staining (red) of Sp7 (e) and Runx2 (f) in the suture mesenchyme of one-month-old Ihh-LacZ mice. Yellow indicates colocalization of fluorescent staining (arrows). (g-l) HE staining (g,h) and microCT analysis (i-l) of one-month-old Gli1-CreERT2;Smofl/fl and Gli1-CreERT2 (ctrl) mice after induction with tamoxifen. Samples were collected 8 months later. Boxed areas in g and h are displayed in the lower panels. MicroCT images in i and k are at the basosphenoid bone position. Arrows indicate basosphenoid bone; asterisks indicate patent sutures. MicroCT images in j and l are at the palatal bone position. Arrows indicate palatal bones; arrowheads indicate presphenoid bones; asterisks indicate patent sutures. Scale bars in panels i, j, k and l, 1mm; other scale bars, 100 μm.

Mentions: Previous studies have proposed that MSCs in the long bone are regulated by a perivascular niche4. We therefore set out to test whether Gli1+ cells in the suture are regulated by the same mechanism. In fact, we found that Gli1+ cells in the suture mesenchyme mainly reside around the midline of the structure and do not show a particular affinity for the vasculature (Figure 5a). After induction, Shh-CreERT2;R26Tdtomatoflox mice do not show any signal in the suture region (Figure 5b), indicating the absence of SHH from the suture mesenchyme, consistent with a previous study32. However, Ihh-LacZ reporter mice revealed Ihh+ cells lining the edges of the calvarial bones (Figure 5c-d). Ihh+ cells are positive for Sp7 and Runx2 (Figure 5e-f) and therefore can be deemed to reside within the osteogenic front in cranial sutures.


The suture provides a niche for mesenchymal stem cells of craniofacial bones.

Zhao H, Feng J, Ho TV, Grimes W, Urata M, Chai Y - Nat. Cell Biol. (2015)

IHH secreted from the osteogenic front signals to Gli1+ cells in the suture mesenchyme and regulates osteogenic lineage differentiation. (a) Immunohistochemical staining of CD31 (green) in the sagittal suture in Gli1-LacZ mice. CD31 labels vasculature. Dotted line outlines the parietal bone. (b) Suture mesenchyme in Shh-CreERT2;Tdtomatofl mice. One-month-old mice were induced and samples were collected two weeks later. (c,d) LacZ staining of the sagittal suture of Ihh-LacZ mice at 1 month of age. Ihh+ cells are detectable at the osteogenic front of the parietal bone (c) but not in the periosteum or dura (d). Dotted line outlines the parietal bone margin. (e,f) Immunohistochemical staining (red) of Sp7 (e) and Runx2 (f) in the suture mesenchyme of one-month-old Ihh-LacZ mice. Yellow indicates colocalization of fluorescent staining (arrows). (g-l) HE staining (g,h) and microCT analysis (i-l) of one-month-old Gli1-CreERT2;Smofl/fl and Gli1-CreERT2 (ctrl) mice after induction with tamoxifen. Samples were collected 8 months later. Boxed areas in g and h are displayed in the lower panels. MicroCT images in i and k are at the basosphenoid bone position. Arrows indicate basosphenoid bone; asterisks indicate patent sutures. MicroCT images in j and l are at the palatal bone position. Arrows indicate palatal bones; arrowheads indicate presphenoid bones; asterisks indicate patent sutures. Scale bars in panels i, j, k and l, 1mm; other scale bars, 100 μm.
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Figure 5: IHH secreted from the osteogenic front signals to Gli1+ cells in the suture mesenchyme and regulates osteogenic lineage differentiation. (a) Immunohistochemical staining of CD31 (green) in the sagittal suture in Gli1-LacZ mice. CD31 labels vasculature. Dotted line outlines the parietal bone. (b) Suture mesenchyme in Shh-CreERT2;Tdtomatofl mice. One-month-old mice were induced and samples were collected two weeks later. (c,d) LacZ staining of the sagittal suture of Ihh-LacZ mice at 1 month of age. Ihh+ cells are detectable at the osteogenic front of the parietal bone (c) but not in the periosteum or dura (d). Dotted line outlines the parietal bone margin. (e,f) Immunohistochemical staining (red) of Sp7 (e) and Runx2 (f) in the suture mesenchyme of one-month-old Ihh-LacZ mice. Yellow indicates colocalization of fluorescent staining (arrows). (g-l) HE staining (g,h) and microCT analysis (i-l) of one-month-old Gli1-CreERT2;Smofl/fl and Gli1-CreERT2 (ctrl) mice after induction with tamoxifen. Samples were collected 8 months later. Boxed areas in g and h are displayed in the lower panels. MicroCT images in i and k are at the basosphenoid bone position. Arrows indicate basosphenoid bone; asterisks indicate patent sutures. MicroCT images in j and l are at the palatal bone position. Arrows indicate palatal bones; arrowheads indicate presphenoid bones; asterisks indicate patent sutures. Scale bars in panels i, j, k and l, 1mm; other scale bars, 100 μm.
Mentions: Previous studies have proposed that MSCs in the long bone are regulated by a perivascular niche4. We therefore set out to test whether Gli1+ cells in the suture are regulated by the same mechanism. In fact, we found that Gli1+ cells in the suture mesenchyme mainly reside around the midline of the structure and do not show a particular affinity for the vasculature (Figure 5a). After induction, Shh-CreERT2;R26Tdtomatoflox mice do not show any signal in the suture region (Figure 5b), indicating the absence of SHH from the suture mesenchyme, consistent with a previous study32. However, Ihh-LacZ reporter mice revealed Ihh+ cells lining the edges of the calvarial bones (Figure 5c-d). Ihh+ cells are positive for Sp7 and Runx2 (Figure 5e-f) and therefore can be deemed to reside within the osteogenic front in cranial sutures.

Bottom Line: Gli1+ cells are typical MSCs in vitro.Ablation of Gli1+ cells leads to craniosynostosis and arrest of skull growth, indicating that these cells are an indispensable stem cell population.Twist1(+/-) mice with craniosynostosis show reduced Gli1+ MSCs in sutures, suggesting that craniosynostosis may result from diminished suture stem cells.

View Article: PubMed Central - PubMed

Affiliation: Center for Craniofacial Molecular Biology, Ostrow School of Dentistry, University of Southern California, 2250 Alcazar Street, CSA 103 Los Angeles, California 90033, USA.

ABSTRACT
Bone tissue undergoes constant turnover supported by stem cells. Recent studies showed that perivascular mesenchymal stem cells (MSCs) contribute to the turnover of long bones. Craniofacial bones are flat bones derived from a different embryonic origin than the long bones. The identity and regulating niche for craniofacial-bone MSCs remain unknown. Here, we identify Gli1+ cells within the suture mesenchyme as the main MSC population for craniofacial bones. They are not associated with vasculature, give rise to all craniofacial bones in the adult and are activated during injury repair. Gli1+ cells are typical MSCs in vitro. Ablation of Gli1+ cells leads to craniosynostosis and arrest of skull growth, indicating that these cells are an indispensable stem cell population. Twist1(+/-) mice with craniosynostosis show reduced Gli1+ MSCs in sutures, suggesting that craniosynostosis may result from diminished suture stem cells. Our study indicates that craniofacial sutures provide a unique niche for MSCs for craniofacial bone homeostasis and repair.

Show MeSH
Related in: MedlinePlus