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Bone Morphogenetic Protein-9 Is a Potent Chondrogenic and Morphogenic Factor for Articular Cartilage Chondroprogenitors

Ben Morgan, Guillermo Bauza-Mayol, Oliver Gardner, YADAN ZHANG, Riccardo Levato, Charles Archer, Rene van Weeren, Jos Malda, Steve Conlan Orcid Logo, Lewis Francis Orcid Logo, Ilyas Khan Orcid Logo

Stem Cells and Development, Volume: 29, Issue: 14

Swansea University Authors: Ben Morgan, Oliver Gardner, YADAN ZHANG, Charles Archer, Steve Conlan Orcid Logo, Lewis Francis Orcid Logo, Ilyas Khan Orcid Logo

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DOI (Published version): 10.1089/scd.2019.0209

Abstract

Articular cartilage contains a subpopulation of tissue-specific progenitors that are an ideal cell type for cell therapies and generating neo-cartilage for tissue engineering applications. However, it is unclear whether the standard chondrogenic medium employing transforming growth factor-β (TGFβ) i...

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Published in: Stem Cells and Development
ISSN: 1547-3287 1557-8534
Published: Mary Ann Liebert Inc 2020
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However, it is unclear whether the standard chondrogenic medium employing transforming growth factor-&#x3B2; (TGF&#x3B2;) isoforms is optimal to differentiate these cells. We therefore used pellet culture to screen progenitors from immature bovine articular cartilage with a number of chondrogenic factors and discovered that bone morphogenetic factor-9 (BMP9) precociously induces their differentiation. This difference was apparent with toluidine blue staining and confirmed by biochemical and transcriptional analyses with BMP9 treated progenitors exhibiting 11-fold and 5-fold greater aggrecan and collagen type II gene expression than TGF&#x3B2;1 treated progenitors. Quantitative gene expression analysis over 14 days highlighted the rapid and phased nature of BMP9 induced chondrogenesis with sequential activation of aggrecan then collagen type II, and negligible collagen type X gene expression. The extracellular matrix of TGF&#x3B2;1treated progenitors analysed using atomic force microscopy was fibrillar and stiff whist BMP9-induced matrix of cells more compliant and correspondingly less fibrillar. Polarised light microscopy revealed an annular pattern of collagen fibril deposition typified by TGF&#x3B2;1 treated pellets, whereas BMP9 treated pellets displayed a birefringence pattern that was more anisotropic. Remarkably, differentiated immature chondrocytes incubated as high-density cultures in vitro with BMP9 generated a pronounced anisotropic organisation of collagen fibrils indistinguishable from mature adult articular cartilage, with cells in deeper zones arranged in columnar fashion. This contrasted with cells grown with TGF&#x3B2;1 where a concentric pattern of collagen fibrils was visualised within tissue pellets. 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spelling 2020-08-10T14:17:20.9390624 v2 54205 2020-05-12 Bone Morphogenetic Protein-9 Is a Potent Chondrogenic and Morphogenic Factor for Articular Cartilage Chondroprogenitors d173b9887192b836956b16035581437c Ben Morgan Ben Morgan true false c498df19a8454afdda6f8f9f75a859da Oliver Gardner Oliver Gardner true false 0b87eada14b5f81ff93ab9f6b30f6294 YADAN ZHANG YADAN ZHANG true false d23ecc9643761bda7acd0f488ed0783e Charles Archer Charles Archer true false 0bb6bd247e32fb4249de62c0013b51cb 0000-0002-2562-3461 Steve Conlan Steve Conlan true false 10f61f9c1248951c1a33f6a89498f37d 0000-0002-7803-7714 Lewis Francis Lewis Francis true false 2536d955ff70e7b77063a8efe9103161 0000-0002-3886-1987 Ilyas Khan Ilyas Khan true false 2020-05-12 MECH Articular cartilage contains a subpopulation of tissue-specific progenitors that are an ideal cell type for cell therapies and generating neo-cartilage for tissue engineering applications. However, it is unclear whether the standard chondrogenic medium employing transforming growth factor-β (TGFβ) isoforms is optimal to differentiate these cells. We therefore used pellet culture to screen progenitors from immature bovine articular cartilage with a number of chondrogenic factors and discovered that bone morphogenetic factor-9 (BMP9) precociously induces their differentiation. This difference was apparent with toluidine blue staining and confirmed by biochemical and transcriptional analyses with BMP9 treated progenitors exhibiting 11-fold and 5-fold greater aggrecan and collagen type II gene expression than TGFβ1 treated progenitors. Quantitative gene expression analysis over 14 days highlighted the rapid and phased nature of BMP9 induced chondrogenesis with sequential activation of aggrecan then collagen type II, and negligible collagen type X gene expression. The extracellular matrix of TGFβ1treated progenitors analysed using atomic force microscopy was fibrillar and stiff whist BMP9-induced matrix of cells more compliant and correspondingly less fibrillar. Polarised light microscopy revealed an annular pattern of collagen fibril deposition typified by TGFβ1 treated pellets, whereas BMP9 treated pellets displayed a birefringence pattern that was more anisotropic. Remarkably, differentiated immature chondrocytes incubated as high-density cultures in vitro with BMP9 generated a pronounced anisotropic organisation of collagen fibrils indistinguishable from mature adult articular cartilage, with cells in deeper zones arranged in columnar fashion. This contrasted with cells grown with TGFβ1 where a concentric pattern of collagen fibrils was visualised within tissue pellets. In summary, BMP9 is a potent chondrogenic factor for articular cartilage progenitors and is also capable of inducing morphogenesis of adult-like cartilage, a highly desirable attribute for in vitro tissue-engineered cartilage. Journal Article Stem Cells and Development 29 14 Mary Ann Liebert Inc 1547-3287 1557-8534 chondroprogenitors, BMP9, GDF2, anisotropic, differentiation, cartilage 28 5 2020 2020-05-28 10.1089/scd.2019.0209 COLLEGE NANME Mechanical Engineering COLLEGE CODE MECH Swansea University UKRI, MR/L02280X/1 2020-08-10T14:17:20.9390624 2020-05-12T11:18:16.8193683 Ben Morgan 1 Guillermo Bauza-Mayol 2 Oliver Gardner 3 YADAN ZHANG 4 Riccardo Levato 5 Charles Archer 6 Rene van Weeren 7 Jos Malda 8 Steve Conlan 0000-0002-2562-3461 9 Lewis Francis 0000-0002-7803-7714 10 Ilyas Khan 0000-0002-3886-1987 11 54205__17452__dc8677f3cbc245e7bcb440ba26e3a4d3.pdf 54205.pdf 2020-06-09T15:42:57.7074682 Output 1659900 application/pdf Version of Record true Released under the terms of a Creative Commons License (CC-BY). true English http://creativecommons.org/licenses/by/4.0
title Bone Morphogenetic Protein-9 Is a Potent Chondrogenic and Morphogenic Factor for Articular Cartilage Chondroprogenitors
spellingShingle Bone Morphogenetic Protein-9 Is a Potent Chondrogenic and Morphogenic Factor for Articular Cartilage Chondroprogenitors
Ben Morgan
Oliver Gardner
YADAN ZHANG
Charles Archer
Steve Conlan
Lewis Francis
Ilyas Khan
title_short Bone Morphogenetic Protein-9 Is a Potent Chondrogenic and Morphogenic Factor for Articular Cartilage Chondroprogenitors
title_full Bone Morphogenetic Protein-9 Is a Potent Chondrogenic and Morphogenic Factor for Articular Cartilage Chondroprogenitors
title_fullStr Bone Morphogenetic Protein-9 Is a Potent Chondrogenic and Morphogenic Factor for Articular Cartilage Chondroprogenitors
title_full_unstemmed Bone Morphogenetic Protein-9 Is a Potent Chondrogenic and Morphogenic Factor for Articular Cartilage Chondroprogenitors
title_sort Bone Morphogenetic Protein-9 Is a Potent Chondrogenic and Morphogenic Factor for Articular Cartilage Chondroprogenitors
author_id_str_mv d173b9887192b836956b16035581437c
c498df19a8454afdda6f8f9f75a859da
0b87eada14b5f81ff93ab9f6b30f6294
d23ecc9643761bda7acd0f488ed0783e
0bb6bd247e32fb4249de62c0013b51cb
10f61f9c1248951c1a33f6a89498f37d
2536d955ff70e7b77063a8efe9103161
author_id_fullname_str_mv d173b9887192b836956b16035581437c_***_Ben Morgan
c498df19a8454afdda6f8f9f75a859da_***_Oliver Gardner
0b87eada14b5f81ff93ab9f6b30f6294_***_YADAN ZHANG
d23ecc9643761bda7acd0f488ed0783e_***_Charles Archer
0bb6bd247e32fb4249de62c0013b51cb_***_Steve Conlan
10f61f9c1248951c1a33f6a89498f37d_***_Lewis Francis
2536d955ff70e7b77063a8efe9103161_***_Ilyas Khan
author Ben Morgan
Oliver Gardner
YADAN ZHANG
Charles Archer
Steve Conlan
Lewis Francis
Ilyas Khan
author2 Ben Morgan
Guillermo Bauza-Mayol
Oliver Gardner
YADAN ZHANG
Riccardo Levato
Charles Archer
Rene van Weeren
Jos Malda
Steve Conlan
Lewis Francis
Ilyas Khan
format Journal article
container_title Stem Cells and Development
container_volume 29
container_issue 14
publishDate 2020
institution Swansea University
issn 1547-3287
1557-8534
doi_str_mv 10.1089/scd.2019.0209
publisher Mary Ann Liebert Inc
document_store_str 1
active_str 0
description Articular cartilage contains a subpopulation of tissue-specific progenitors that are an ideal cell type for cell therapies and generating neo-cartilage for tissue engineering applications. However, it is unclear whether the standard chondrogenic medium employing transforming growth factor-β (TGFβ) isoforms is optimal to differentiate these cells. We therefore used pellet culture to screen progenitors from immature bovine articular cartilage with a number of chondrogenic factors and discovered that bone morphogenetic factor-9 (BMP9) precociously induces their differentiation. This difference was apparent with toluidine blue staining and confirmed by biochemical and transcriptional analyses with BMP9 treated progenitors exhibiting 11-fold and 5-fold greater aggrecan and collagen type II gene expression than TGFβ1 treated progenitors. Quantitative gene expression analysis over 14 days highlighted the rapid and phased nature of BMP9 induced chondrogenesis with sequential activation of aggrecan then collagen type II, and negligible collagen type X gene expression. The extracellular matrix of TGFβ1treated progenitors analysed using atomic force microscopy was fibrillar and stiff whist BMP9-induced matrix of cells more compliant and correspondingly less fibrillar. Polarised light microscopy revealed an annular pattern of collagen fibril deposition typified by TGFβ1 treated pellets, whereas BMP9 treated pellets displayed a birefringence pattern that was more anisotropic. Remarkably, differentiated immature chondrocytes incubated as high-density cultures in vitro with BMP9 generated a pronounced anisotropic organisation of collagen fibrils indistinguishable from mature adult articular cartilage, with cells in deeper zones arranged in columnar fashion. This contrasted with cells grown with TGFβ1 where a concentric pattern of collagen fibrils was visualised within tissue pellets. In summary, BMP9 is a potent chondrogenic factor for articular cartilage progenitors and is also capable of inducing morphogenesis of adult-like cartilage, a highly desirable attribute for in vitro tissue-engineered cartilage.
published_date 2020-05-28T04:07:35Z
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score 11.037581

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