Additive effects of sonic hedgehog and nell-1 signaling in osteogenic versus adipogenic differentiation of human adipose-derived stromal cells

Aaron James, Shen Pang, Asal Askarinam, Mirko Corselli, Janette N. Zara, Raghav Goyal, Le Chang, Angel Pan, Jia Shen, Wei Yuan, David Stoker, Xinli Zhang, John S. Adams, Kang Ting, Chia Soo

Research output: Contribution to journalArticle

Abstract

A theoretical inverse relationship exists between osteogenic (bone forming) and adipogenic (fat forming) mesenchymal stem cell (MSC) differentiation. This inverse relationship in theory partially underlies the clinical entity of osteoporosis, in which marrow MSCs have a preference for adipose differentiation that increases with age. Two pro-osteogenic cytokines have been recently studied that each also possesses antiadipogenic properties: Sonic Hedgehog (SHH) and NELL-1 proteins. In the present study, we assayed the potential additive effects of the biologically active N-terminus of SHH (SHH-N) and NELL-1 protein on osteogenic and adipogenic differentiation of human primary adipose-derived stromal cell (hASCs). We observed that both recombinant SHH-N and NELL-1 protein significantly enhanced osteogenic differentiation and reduced adipose differentiation across all markers examined (alkaline phosphatase, Alizarin red and Oil red O staining, and osteogenic gene expression). Moreover, SHH-N and NELL-1 directed signaling produced additive effects on the pro-osteogenic and antiadipogenic differentiation of hASCs. NELL-1 treatment increased Hedgehog signaling pathway expression; coapplication of the Smoothened antagonist Cyclopamine reversed the pro-osteogenic effect of NELL-1. In summary, Hedgehog and Nell-1 signaling exert additive effects on the pro-osteogenic and antiadipogenic differentiation of ASCs. These studies suggest that the combination cytokines SHH-N+NELL-1 may represent a viable future technique for inducing the osteogenic differentiation of MSCs.

Original languageEnglish (US)
Pages (from-to)2170-2178
Number of pages9
JournalStem Cells and Development
Volume21
Issue number12
DOIs
StatePublished - Aug 10 2012
Externally publishedYes

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Stromal Cells
Bone Morphogenetic Protein 7
Cytokines
Mesenchymal Stromal Cells
Osteoporosis
Alkaline Phosphatase
Cell Differentiation
Proteins
Bone Marrow
Fats
Staining and Labeling
Gene Expression
Bone and Bones
cyclopamine
alizarin
oil red O

ASJC Scopus subject areas

  • Hematology
  • Developmental Biology
  • Cell Biology

Cite this

Additive effects of sonic hedgehog and nell-1 signaling in osteogenic versus adipogenic differentiation of human adipose-derived stromal cells. / James, Aaron; Pang, Shen; Askarinam, Asal; Corselli, Mirko; Zara, Janette N.; Goyal, Raghav; Chang, Le; Pan, Angel; Shen, Jia; Yuan, Wei; Stoker, David; Zhang, Xinli; Adams, John S.; Ting, Kang; Soo, Chia.

In: Stem Cells and Development, Vol. 21, No. 12, 10.08.2012, p. 2170-2178.

Research output: Contribution to journalArticle

James, A, Pang, S, Askarinam, A, Corselli, M, Zara, JN, Goyal, R, Chang, L, Pan, A, Shen, J, Yuan, W, Stoker, D, Zhang, X, Adams, JS, Ting, K & Soo, C 2012, 'Additive effects of sonic hedgehog and nell-1 signaling in osteogenic versus adipogenic differentiation of human adipose-derived stromal cells', Stem Cells and Development, vol. 21, no. 12, pp. 2170-2178. https://doi.org/10.1089/scd.2011.0461
James, Aaron ; Pang, Shen ; Askarinam, Asal ; Corselli, Mirko ; Zara, Janette N. ; Goyal, Raghav ; Chang, Le ; Pan, Angel ; Shen, Jia ; Yuan, Wei ; Stoker, David ; Zhang, Xinli ; Adams, John S. ; Ting, Kang ; Soo, Chia. / Additive effects of sonic hedgehog and nell-1 signaling in osteogenic versus adipogenic differentiation of human adipose-derived stromal cells. In: Stem Cells and Development. 2012 ; Vol. 21, No. 12. pp. 2170-2178.
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AU - Pang, Shen

AU - Askarinam, Asal

AU - Corselli, Mirko

AU - Zara, Janette N.

AU - Goyal, Raghav

AU - Chang, Le

AU - Pan, Angel

AU - Shen, Jia

AU - Yuan, Wei

AU - Stoker, David

AU - Zhang, Xinli

AU - Adams, John S.

AU - Ting, Kang

AU - Soo, Chia

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AB - A theoretical inverse relationship exists between osteogenic (bone forming) and adipogenic (fat forming) mesenchymal stem cell (MSC) differentiation. This inverse relationship in theory partially underlies the clinical entity of osteoporosis, in which marrow MSCs have a preference for adipose differentiation that increases with age. Two pro-osteogenic cytokines have been recently studied that each also possesses antiadipogenic properties: Sonic Hedgehog (SHH) and NELL-1 proteins. In the present study, we assayed the potential additive effects of the biologically active N-terminus of SHH (SHH-N) and NELL-1 protein on osteogenic and adipogenic differentiation of human primary adipose-derived stromal cell (hASCs). We observed that both recombinant SHH-N and NELL-1 protein significantly enhanced osteogenic differentiation and reduced adipose differentiation across all markers examined (alkaline phosphatase, Alizarin red and Oil red O staining, and osteogenic gene expression). Moreover, SHH-N and NELL-1 directed signaling produced additive effects on the pro-osteogenic and antiadipogenic differentiation of hASCs. NELL-1 treatment increased Hedgehog signaling pathway expression; coapplication of the Smoothened antagonist Cyclopamine reversed the pro-osteogenic effect of NELL-1. In summary, Hedgehog and Nell-1 signaling exert additive effects on the pro-osteogenic and antiadipogenic differentiation of ASCs. These studies suggest that the combination cytokines SHH-N+NELL-1 may represent a viable future technique for inducing the osteogenic differentiation of MSCs.

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