NELL-1 induces Sca-1+ mesenchymal progenitor cell expansion in models of bone maintenance and repair
Aaron W. James, … , Xinli Zhang, Chia Soo
Aaron W. James, … , Xinli Zhang, Chia Soo
Published June 15, 2017
Citation Information: JCI Insight. 2017;2(12):e92573. doi:10.1172/jci.insight.92573.
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Categories: Research Article Bone biology Cell biology

NELL-1 induces Sca-1+ mesenchymal progenitor cell expansion in models of bone maintenance and repair

Abstract

NELL-1 is a secreted, osteogenic protein first discovered to control ossification of the cranial skeleton. Recently, NELL-1 has been implicated in bone maintenance. However, the cellular determinants of NELL-1’s bone-forming effects are still unknown. Here, recombinant human NELL-1 (rhNELL-1) implantation was examined in a clinically relevant nonhuman primate lumbar spinal fusion model. Prolonged rhNELL-1 protein release was achieved using an apatite-coated β-tricalcium phosphate carrier, resulting in a local influx of stem cell antigen-1–positive (Sca-1+) mesenchymal progenitor cells (MPCs), and complete osseous fusion across all samples (100% spinal fusion rate). Murine studies revealed that Nell-1 haploinsufficiency results in marked reductions in the numbers of Sca-1+CD45–CD31– bone marrow MPCs associated with low bone mass. Conversely, rhNELL-1 systemic administration in mice showed a marked anabolic effect accompanied by increased numbers of Sca-1+CD45–CD31– bone marrow MPCs. Mechanistically, rhNELL-1 induces Sca-1 transcription among MPCs, in a process requiring intact Wnt/β-catenin signaling. In summary, NELL-1 effectively induces bone formation across small and large animal models either via local implantation or intravenous delivery. NELL-1 induces an expansion of a bone marrow subset of MPCs with Sca-1 expression. These findings provide compelling justification for the clinical translation of a NELL-1–based therapy for local or systemic bone formation.

Authors

Aaron W. James, Jia Shen, Rebecca Tsuei, Alan Nguyen, Kevork Khadarian, Carolyn A. Meyers, Hsin Chuan Pan, Weiming Li, Jin H. Kwak, Greg Asatrian, Cymbeline T. Culiat, Min Lee, Kang Ting, Xinli Zhang, Chia Soo

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Figure 1

RhNELL-1 application in nonhuman primate lumbar spinal fusion: radiographic analysis.

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RhNELL-1 application in nonhuman primate lumbar spinal fusion: radiograp...
(A) Schematic diagram of nonhuman primate spinal fusion model. The rhNELL-1–based bone graft substitute was inserted within the spinal fusion cage. Contents of the spinal fusion cage are summarized in Table 1. Postoperative high-resolution microCT imaging was performed after 3 months. (B) Representative 3D anterior-posterior reconstructions of new bone within the interbody cage between lumbar vertebrae from PBS, 1.0 mg/ml rhNELL-1, and 1.7 mg/ml rhNELL-1 treatment groups at 3 postoperative months. (C–G) MicroCT analyses of the lumbar vertebral spinal fusion segment, including (C) bone mineral density (BMD), (D) bone volume/total volume (BV/TV), (E) trabecular bone thickness (Tb.Th), (F) trabecular spacing (Tb.Sp), and (G) trabecular number (Tb.N). (H and I) Computer-simulated biomechanical finite element analysis (FEA) and quantification of von Mises stress. Red color indicates areas of high calculated stress. n = 4 spinal fusion levels per treatment group, performed in single replicate. Values reported as mean ± SEM. *P < 0.05, **P < 0.01 in comparison with the PBS group using a 1-way ANOVA followed by a post-hoc Tukey’s test. #P < 0.05, ##P < 0.01 in comparison with the 1.0 mg/ml rhNELL-1 group. Scale bars: 1 mm.