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

Aaron 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJCI insight
Volume2
Issue number12
DOIs
StatePublished - Jun 15 2017

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Mesenchymal Stromal Cells
Maintenance
Bone and Bones
Osteogenesis
Spinal Fusion
Bone Marrow
Phosphate Transport Proteins
Haploinsufficiency
Anabolic Agents
Catenins
Apatites
Skeleton
Primates
Proteins
Stem Cells
Animal Models
Antigens
Therapeutics

Keywords

  • Bone Biology
  • Cell Biology

Cite this

NELL-1 induces Sca-1+ mesenchymal progenitor cell expansion in models of bone maintenance and repair. / James, Aaron; Shen, Jia; Tsuei, Rebecca; Nguyen, Alan; Khadarian, Kevork; Meyers, Carolyn A.; Pan, Hsin Chuan; Li, Weiming; Kwak, Jin H.; Asatrian, Greg; Culiat, Cymbeline T.; Lee, Min; Ting, Kang; Zhang, Xinli; Soo, Chia.

In: JCI insight, Vol. 2, No. 12, 15.06.2017.

Research output: Contribution to journalArticle

James, A, Shen, J, Tsuei, R, Nguyen, A, Khadarian, K, Meyers, CA, Pan, HC, Li, W, Kwak, JH, Asatrian, G, Culiat, CT, Lee, M, Ting, K, Zhang, X & Soo, C 2017, 'NELL-1 induces Sca-1+ mesenchymal progenitor cell expansion in models of bone maintenance and repair', JCI insight, vol. 2, no. 12. https://doi.org/10.1172/jci.insight.92573
James, Aaron ; Shen, Jia ; Tsuei, Rebecca ; Nguyen, Alan ; Khadarian, Kevork ; Meyers, Carolyn A. ; Pan, Hsin Chuan ; Li, Weiming ; Kwak, Jin H. ; Asatrian, Greg ; Culiat, Cymbeline T. ; Lee, Min ; Ting, Kang ; Zhang, Xinli ; Soo, Chia. / NELL-1 induces Sca-1+ mesenchymal progenitor cell expansion in models of bone maintenance and repair. In: JCI insight. 2017 ; Vol. 2, No. 12.
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AU - James, Aaron

AU - Shen, Jia

AU - Tsuei, Rebecca

AU - Nguyen, Alan

AU - Khadarian, Kevork

AU - Meyers, Carolyn A.

AU - Pan, Hsin Chuan

AU - Li, Weiming

AU - Kwak, Jin H.

AU - Asatrian, Greg

AU - Culiat, Cymbeline T.

AU - Lee, Min

AU - Ting, Kang

AU - Zhang, Xinli

AU - Soo, Chia

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N2 - 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.

AB - 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.

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