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. https://doi.org/10.1172/jci.insight.92573.
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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 2

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

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RhNELL-1 application in nonhuman primate lumbar spinal fusion: histologi...
(A) Goldner’s modified trichrome (GMT) and von Kossa-MacNeal’s tetrachrome (VKMT) staining of nonhuman lumbar vertebral spinal fusion segment from PBS, 1.0 mg/ml rhNELL-1, and 1.7 mg/ml rhNELL-1 treatment groups. Images are shown in coronal cross section and include the centrally located spinal fusion segment, with each vertebral body on the lower and upper aspects of the image. Scale bars: 1 mm. (B) Quantification of VKMT histomorphometric analysis. Three random fields within the spinal fusion segment were analyzed per slide, with 2–3 slides per sample. (C) Representative H&E staining of lumbar vertebral spinal fusion segment from PBS, 1.0 mg/ml rhNELL-1, and 1.7 mg/ml rhNELL-1 treatment groups. n = 4 spinal fusion levels per treatment group, performed in single replicate. **P < 0.01 compared with the PBS group. ##P < 0.01 compared with the 1.0 mg/ml rhNELL-1 group, analyzed using a 1-way ANOVA followed by a post-hoc Tukey’s test. Bm, Bone marrow; DBX, demineralized bone matrix putty; Tb, trabecular bone.