Proliferation and osteogenic differentiation of mesenchymal stem cells induced by a short isoform of NELL-1.
Neural epidermal growth factor-like (NEL)-like protein 1 (NELL-1) has been identified as an osteoinductive differentiation factor that promotes mesenchymal stem cell (MSC) osteogenic differentiation. In addition to full-length NELL-1, there are several NELL-1-related transcripts reported. We used rapid amplification of cDNA ends to recover potential cDNA of NELL-1 isoforms. A NELL-1 isoform with the N-terminal 240 amino acid (aa) residues truncated was identified. While full-length NELL-1 that contains 810 aa residues (NELL-1810 ) plays an important role in embryologic skeletal development, the N-terminal-truncated NELL-1 isoform (NELL-1570 ) was expressed postnatally. Similar to NELL-1810 , NELL-1570 induced MSC osteogenic differentiation. In addition, NELL-1570 significantly stimulated MSC proliferation in multiple MSC-like populations such as murine C3H10T1/2 MSC cell line, mouse primary MSCs, and perivascular stem cells, which is a type of stem cells proposed as the perivascular origin of MSCs. In contrast, NELL-1810 demonstrated only limited stimulation of MSC proliferation. Similar to NELL-1810 , NELL-1570 was found to be secreted from host cells. Both NELL-1570 expression lentiviral vector and column-purified recombinant protein NELL-1570 demonstrated almost identical effects in MSC proliferation and osteogenic differentiation, suggesting that NELL-1570 may function as a pro-osteogenic growth factor. In vivo, NELL-1570 induced significant calvarial defect regeneration accompanied by increased cell proliferation. Thus, NELL-1570 has the potential to be used for cell-based or hormone-based therapy of bone regeneration.
UCLA and Orthopaedic Hospital Department of Orthopaedic Surgery and the Orthopaedic Hospital Research Center, University of California, Los Angeles, California, USA.
Shen
S
Pang
Jia
J
Shen
Yi
Y
Liu
Feng
F
Chen
Zhong
Z
Zheng
Aaron W
AW
James
Ching-Yun
CY
Hsu
Hong
H
Zhang
Kevin S
KS
Lee
Chunling
C
Wang
Chenshuang
C
Li
Xuepeng
X
Chen
Haichao
H
Jia
Xinli
X
Zhang
Chia
C
Soo
Kang
K
Ting
D000818:Animals; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D010012:Osteogenesis / Q000502:physiology*; D020033:Protein Isoforms; D051381:Rats; D017207:Rats, Sprague-Dawley
D002135:Calcium-Binding Proteins; D006023:Glycoproteins; C513122:Nell1 protein, mouse; C484480:Nell1 protein, rat; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms
MSC proliferation; NELL-1; Osteogenesis; Secretory protein; Short NELL-1 isoform