Parenchymal and stromal tissue regeneration of tooth organ by pivotal signals reinstated in decellularized matrix

Ling He, Jian Zhou, Mo Chen, Chyuan Sheng Lin, Sahng G. Kim, Yue Zhou, Lusai Xiang, Ming Xie, Hanying Bai, Hai Yao, Changcheng Shi, Paulo Coelho, Timothy Bromage, Bin Hu, Nick Tovar, Lukasz Witek, Jiaqian Wu, Kenian Chen, Wei Gu, Jinxuan ZhengTzong Jen Sheu, Juan Zhong, Jin Wen, Yuting Niu, Bin Cheng, Qimei Gong, David M. Owens, Milda Stanislauskas, Jasmine Pei, Gregory Chotkowski, Sainan Wang, Guodong Yang, David J. Zegarelli, Xin Shi, Myron Finkel, Wen Zhang, Junyuan Li, Jiayi Cheng, Dennis P. Tarnow, Xuedong Zhou, Zuolin Wang, Xinquan Jiang, Alexander Romanov, David W. Rowe, Songlin Wang, Ling Ye, Junqi Ling, Jeremy Mao

Research output: Contribution to journalArticle

Abstract

Cells are transplanted to regenerate an organs’ parenchyma, but how transplanted parenchymal cells induce stromal regeneration is elusive. Despite the common use of a decellularized matrix, little is known as to the pivotal signals that must be restored for tissue or organ regeneration. We report that Alx3, a developmentally important gene, orchestrated adult parenchymal and stromal regeneration by directly transactivating Wnt3a and vascular endothelial growth factor. In contrast to the modest parenchyma formed by native adult progenitors, Alx3-restored cells in decellularized scaffolds not only produced vascularized stroma that involved vascular endothelial growth factor signalling, but also parenchymal dentin via the Wnt/β–catenin pathway. In an orthotopic large-animal model following parenchyma and stroma ablation, Wnt3a-recruited endogenous cells regenerated neurovascular stroma and differentiated into parenchymal odontoblast-like cells that extended the processes into newly formed dentin with a structure–mechanical equivalency to native dentin. Thus, the Alx3–Wnt3a axis enables postnatal progenitors with a modest innate regenerative capacity to regenerate adult tissues. Depleted signals in the decellularized matrix may be reinstated by a developmentally pivotal gene or corresponding protein.

Original languageEnglish (US)
Pages (from-to)627-637
Number of pages11
JournalNature Materials
Volume18
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Tissue regeneration
teeth
regeneration
organs
Vascular Endothelial Growth Factor A
Genes
Tissue
Catenins
matrices
Ablation
cells
Scaffolds
Animals
genes
Proteins
animal models
ablation
Intercellular Signaling Peptides and Proteins
proteins

ASJC Scopus subject areas

  • Chemistry(all)
  • Materials Science(all)
  • Condensed Matter Physics
  • Mechanics of Materials
  • Mechanical Engineering

Cite this

Parenchymal and stromal tissue regeneration of tooth organ by pivotal signals reinstated in decellularized matrix. / He, Ling; Zhou, Jian; Chen, Mo; Lin, Chyuan Sheng; Kim, Sahng G.; Zhou, Yue; Xiang, Lusai; Xie, Ming; Bai, Hanying; Yao, Hai; Shi, Changcheng; Coelho, Paulo; Bromage, Timothy; Hu, Bin; Tovar, Nick; Witek, Lukasz; Wu, Jiaqian; Chen, Kenian; Gu, Wei; Zheng, Jinxuan; Sheu, Tzong Jen; Zhong, Juan; Wen, Jin; Niu, Yuting; Cheng, Bin; Gong, Qimei; Owens, David M.; Stanislauskas, Milda; Pei, Jasmine; Chotkowski, Gregory; Wang, Sainan; Yang, Guodong; Zegarelli, David J.; Shi, Xin; Finkel, Myron; Zhang, Wen; Li, Junyuan; Cheng, Jiayi; Tarnow, Dennis P.; Zhou, Xuedong; Wang, Zuolin; Jiang, Xinquan; Romanov, Alexander; Rowe, David W.; Wang, Songlin; Ye, Ling; Ling, Junqi; Mao, Jeremy.

In: Nature Materials, Vol. 18, No. 6, 01.06.2019, p. 627-637.

Research output: Contribution to journalArticle

He, L, Zhou, J, Chen, M, Lin, CS, Kim, SG, Zhou, Y, Xiang, L, Xie, M, Bai, H, Yao, H, Shi, C, Coelho, P, Bromage, T, Hu, B, Tovar, N, Witek, L, Wu, J, Chen, K, Gu, W, Zheng, J, Sheu, TJ, Zhong, J, Wen, J, Niu, Y, Cheng, B, Gong, Q, Owens, DM, Stanislauskas, M, Pei, J, Chotkowski, G, Wang, S, Yang, G, Zegarelli, DJ, Shi, X, Finkel, M, Zhang, W, Li, J, Cheng, J, Tarnow, DP, Zhou, X, Wang, Z, Jiang, X, Romanov, A, Rowe, DW, Wang, S, Ye, L, Ling, J & Mao, J 2019, 'Parenchymal and stromal tissue regeneration of tooth organ by pivotal signals reinstated in decellularized matrix', Nature Materials, vol. 18, no. 6, pp. 627-637. https://doi.org/10.1038/s41563-019-0368-6
He, Ling ; Zhou, Jian ; Chen, Mo ; Lin, Chyuan Sheng ; Kim, Sahng G. ; Zhou, Yue ; Xiang, Lusai ; Xie, Ming ; Bai, Hanying ; Yao, Hai ; Shi, Changcheng ; Coelho, Paulo ; Bromage, Timothy ; Hu, Bin ; Tovar, Nick ; Witek, Lukasz ; Wu, Jiaqian ; Chen, Kenian ; Gu, Wei ; Zheng, Jinxuan ; Sheu, Tzong Jen ; Zhong, Juan ; Wen, Jin ; Niu, Yuting ; Cheng, Bin ; Gong, Qimei ; Owens, David M. ; Stanislauskas, Milda ; Pei, Jasmine ; Chotkowski, Gregory ; Wang, Sainan ; Yang, Guodong ; Zegarelli, David J. ; Shi, Xin ; Finkel, Myron ; Zhang, Wen ; Li, Junyuan ; Cheng, Jiayi ; Tarnow, Dennis P. ; Zhou, Xuedong ; Wang, Zuolin ; Jiang, Xinquan ; Romanov, Alexander ; Rowe, David W. ; Wang, Songlin ; Ye, Ling ; Ling, Junqi ; Mao, Jeremy. / Parenchymal and stromal tissue regeneration of tooth organ by pivotal signals reinstated in decellularized matrix. In: Nature Materials. 2019 ; Vol. 18, No. 6. pp. 627-637.
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abstract = "Cells are transplanted to regenerate an organs’ parenchyma, but how transplanted parenchymal cells induce stromal regeneration is elusive. Despite the common use of a decellularized matrix, little is known as to the pivotal signals that must be restored for tissue or organ regeneration. We report that Alx3, a developmentally important gene, orchestrated adult parenchymal and stromal regeneration by directly transactivating Wnt3a and vascular endothelial growth factor. In contrast to the modest parenchyma formed by native adult progenitors, Alx3-restored cells in decellularized scaffolds not only produced vascularized stroma that involved vascular endothelial growth factor signalling, but also parenchymal dentin via the Wnt/β–catenin pathway. In an orthotopic large-animal model following parenchyma and stroma ablation, Wnt3a-recruited endogenous cells regenerated neurovascular stroma and differentiated into parenchymal odontoblast-like cells that extended the processes into newly formed dentin with a structure–mechanical equivalency to native dentin. Thus, the Alx3–Wnt3a axis enables postnatal progenitors with a modest innate regenerative capacity to regenerate adult tissues. Depleted signals in the decellularized matrix may be reinstated by a developmentally pivotal gene or corresponding protein.",
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T1 - Parenchymal and stromal tissue regeneration of tooth organ by pivotal signals reinstated in decellularized matrix

AU - He, Ling

AU - Zhou, Jian

AU - Chen, Mo

AU - Lin, Chyuan Sheng

AU - Kim, Sahng G.

AU - Zhou, Yue

AU - Xiang, Lusai

AU - Xie, Ming

AU - Bai, Hanying

AU - Yao, Hai

AU - Shi, Changcheng

AU - Coelho, Paulo

AU - Bromage, Timothy

AU - Hu, Bin

AU - Tovar, Nick

AU - Witek, Lukasz

AU - Wu, Jiaqian

AU - Chen, Kenian

AU - Gu, Wei

AU - Zheng, Jinxuan

AU - Sheu, Tzong Jen

AU - Zhong, Juan

AU - Wen, Jin

AU - Niu, Yuting

AU - Cheng, Bin

AU - Gong, Qimei

AU - Owens, David M.

AU - Stanislauskas, Milda

AU - Pei, Jasmine

AU - Chotkowski, Gregory

AU - Wang, Sainan

AU - Yang, Guodong

AU - Zegarelli, David J.

AU - Shi, Xin

AU - Finkel, Myron

AU - Zhang, Wen

AU - Li, Junyuan

AU - Cheng, Jiayi

AU - Tarnow, Dennis P.

AU - Zhou, Xuedong

AU - Wang, Zuolin

AU - Jiang, Xinquan

AU - Romanov, Alexander

AU - Rowe, David W.

AU - Wang, Songlin

AU - Ye, Ling

AU - Ling, Junqi

AU - Mao, Jeremy

PY - 2019/6/1

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N2 - Cells are transplanted to regenerate an organs’ parenchyma, but how transplanted parenchymal cells induce stromal regeneration is elusive. Despite the common use of a decellularized matrix, little is known as to the pivotal signals that must be restored for tissue or organ regeneration. We report that Alx3, a developmentally important gene, orchestrated adult parenchymal and stromal regeneration by directly transactivating Wnt3a and vascular endothelial growth factor. In contrast to the modest parenchyma formed by native adult progenitors, Alx3-restored cells in decellularized scaffolds not only produced vascularized stroma that involved vascular endothelial growth factor signalling, but also parenchymal dentin via the Wnt/β–catenin pathway. In an orthotopic large-animal model following parenchyma and stroma ablation, Wnt3a-recruited endogenous cells regenerated neurovascular stroma and differentiated into parenchymal odontoblast-like cells that extended the processes into newly formed dentin with a structure–mechanical equivalency to native dentin. Thus, the Alx3–Wnt3a axis enables postnatal progenitors with a modest innate regenerative capacity to regenerate adult tissues. Depleted signals in the decellularized matrix may be reinstated by a developmentally pivotal gene or corresponding protein.

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