NELL-1 induces Sca-1+ mesenchymal progenitor cell expansion in models of bone maintenance and repair
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
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
View: Text | PDF
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

×

Figure 5

RhNELL-1 systemic injection in mouse: radiographic analysis.

Options: View larger image (or click on image) Download as PowerPoint
RhNELL-1 systemic injection in mouse: radiographic analysis. (A) MicroCT...
(A) MicroCT analyses of mice injected with PBS or rhNELL-1 (1.25 mg/kg). (B–G) Absolute change in bone mineral density (BMD), bone volume (BV), bone volume/tissue volume (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), and trabecular spacing (Tb.Sp) among control- and rhNELL-1–treated distal femoral metaphysis by microCT quantification. (H and I) Calcein/alizarin red complex on bone labeling and quantification of mineral apposition rate (MAR) and bone formation rate (BFR). Red and green arrows highlight the space between fluorochrome labels. Scale bar: 25 μm. (J and K) Finite element analysis (FEA) and quantification of von Mises stress within the femoral midshaft. Data reported as mean ± SEM. n = 5–6 samples per group, single replicate. *P < 0.05, **P < 0.01 compared with the PBS group, using a 2-tailed Student’s t test.