TY - JOUR
T1 - Progenitors in peripheral nerves launch heterotopic ossification
AU - Olmsted-Davis, Elizabeth A.
AU - Salisbury, Elizabeth A.
AU - Hoang, Diana
AU - Davis, Eleanor L.
AU - Lazard, Zawaunyka
AU - Sonnet, Corinne
AU - Davis, Thomas A.
AU - Forsberg, Jonathan A.
AU - Davis, Alan R.
N1 - Publisher Copyright:
© AlphaMed Press and 2017 The Authors.
PY - 2017/4
Y1 - 2017/4
N2 - Studies presented here, using a murine model of bone morphogenetic protein type 2 (BMP2)-induced heterotopic ossification (HO) show that the protein initiates HO by signaling through progenitors in the endoneurium of peripheral nerves. In the mouse, these cells were identified in the endoneurium one day after BMP2 induction using antibody against phosphoSMAD (PS) 1, 5, and 8. Studies conducted in a tracking mouse that contains a tamoxifen-regulated Wnt1-Cre recombinase crossed with a td Tomato red (TR) reporter (Wnt1CreErt:Ai9Tm) confirmed their neural origin. In this model both BMP2 induction and tamoxifen are absolutely required to induce TR. SP71(osterix1)TR1 cells were found in the endoneurium on day 1 and associated with bone on day 7. Quantification of TR1 and TR2 cells isolated by fluorescence-activated cell sorting showed that all SP71 cells were found in the TR1 population, whereas only about 80% of the TR1 cells expressed SP7. Pre-chondrocytes (Sox 91) and transient brown fat (tBAT, UCP11) also coexpressed TR, suggesting that the progenitor in nerves is multi-potential. The endoneurium of human nerves near the site of HO contained many PS1 cells, and SP71 cells were found in nerves and on bone in tissue from patients with HO. Control tissues and nerves did not contain these PS1 and SP71 cells. Some osteoblasts on bone from patients with HO were positive for PS, suggesting the continued presence of BMP during bone formation. The data suggests that the progenitors for HO are derived from the endoneurium in both the mouse model of HO and in humans with HO.
AB - Studies presented here, using a murine model of bone morphogenetic protein type 2 (BMP2)-induced heterotopic ossification (HO) show that the protein initiates HO by signaling through progenitors in the endoneurium of peripheral nerves. In the mouse, these cells were identified in the endoneurium one day after BMP2 induction using antibody against phosphoSMAD (PS) 1, 5, and 8. Studies conducted in a tracking mouse that contains a tamoxifen-regulated Wnt1-Cre recombinase crossed with a td Tomato red (TR) reporter (Wnt1CreErt:Ai9Tm) confirmed their neural origin. In this model both BMP2 induction and tamoxifen are absolutely required to induce TR. SP71(osterix1)TR1 cells were found in the endoneurium on day 1 and associated with bone on day 7. Quantification of TR1 and TR2 cells isolated by fluorescence-activated cell sorting showed that all SP71 cells were found in the TR1 population, whereas only about 80% of the TR1 cells expressed SP7. Pre-chondrocytes (Sox 91) and transient brown fat (tBAT, UCP11) also coexpressed TR, suggesting that the progenitor in nerves is multi-potential. The endoneurium of human nerves near the site of HO contained many PS1 cells, and SP71 cells were found in nerves and on bone in tissue from patients with HO. Control tissues and nerves did not contain these PS1 and SP71 cells. Some osteoblasts on bone from patients with HO were positive for PS, suggesting the continued presence of BMP during bone formation. The data suggests that the progenitors for HO are derived from the endoneurium in both the mouse model of HO and in humans with HO.
KW - Blood-nerve barrier
KW - Bone morphogenetic type 2
KW - Heterotopic ossification
KW - Neural stem cells
KW - Trauma
UR - http://www.scopus.com/inward/record.url?scp=85017532222&partnerID=8YFLogxK
U2 - 10.1002/sctm.16-0347
DO - 10.1002/sctm.16-0347
M3 - Article
C2 - 28198109
AN - SCOPUS:85017532222
SN - 2157-6564
VL - 6
SP - 1109
EP - 1119
JO - Stem Cells Translational Medicine
JF - Stem Cells Translational Medicine
IS - 4
ER -