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Guo Q, Wang Z, Li J, Ma C, Zheng J, Ba H, Zhang G, Li C. BRCA1 is involved in sustaining rapid antler growth possibly via balancing of the p53/endoplasmic reticulum stress signaling pathway. Biol Direct 2025; 20:13. [PMID: 39849553 PMCID: PMC11758741 DOI: 10.1186/s13062-025-00606-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 01/14/2025] [Indexed: 01/25/2025] Open
Abstract
BACKGROUND Regeneration is the preferred approach to restore the structure and function after tissue damage. Rapid proliferation of cells over the site of damage is integral to the process of regeneration. However, even subtle mutations in proliferating cells may cause detrimental effects by eliciting abnormal differentiation. Interestingly deer antlers, arguably the fastest regenerating mammalian tissue, have not been reported, thus far, to grow malignant tumors. They provide a mammalian model to understand the possible mechanism by which rapid regeneration is achieved while avoiding the development of malignancies. Antler regeneration is based on the proliferation and differentiation of antler stem cells (AnSCs). RESULTS We identified 39 hub genes which may function in regulating the balance between rapid proliferation and genomic stability in the AnSCs during antler regeneration. Among these 39 genes, the tumor suppressor gene, BRCA1, was found to be more sensitive to DNA damage in the AnSCs compared to that in the deer somatic cells, and BRCA1 deletion in the AnSCs via CRISPR/Cas9 resulted in significantly higher levels of DNA damage. Lack of BRCA1 promoted cell apoptosis and cell senescence and inhibited cell proliferation and cell self-renewal. RNA-seq results showed that in the absence of BRCA1, the p53 signaling pathway was significantly up-regulated. Associated with this change, the cell apoptosis and cell senescence-relevant-genes, CDKN1A, CDKN2A and Fas were over expressed, but the expression of cell-cycle-progression-related genes was inhibited. In addition, BRCA1 expression levels were found to be more sensitive to endoplasmic reticulum stress (ERS) in the AnSCs compared to the somatic cells. Deletion of BRCA1 gene aggravated ERS and ERS-induced cell apoptosis. CONCLUSIONS Our results revealed that BRCA1 is involved in sustaining rapid antler growth possibly via promotion of DNA damage repair that acts to maintain genome stability while protecting cells from p53/ERS-induced cell death. Understanding the mechanisms underlying the role played by BRCA1 in the process of antler regeneration is of great significance not only for regenerative medicine, but also for the understanding of cancer development.
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Affiliation(s)
- Qianqian Guo
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China
| | - Zhen Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China
| | - Jiping Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China
| | - Chao Ma
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China
| | - Junjun Zheng
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, Jilin, China
| | - Hengxing Ba
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China
| | - Guokun Zhang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China.
| | - Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China.
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Guo Q, Zhang G, Ren J, Li J, Wang Z, Ba H, Ye Z, Wang Y, Zheng J, Li C. Systemic factors associated with antler growth promote complete wound healing. NPJ Regen Med 2025; 10:4. [PMID: 39833274 PMCID: PMC11756403 DOI: 10.1038/s41536-025-00391-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 01/10/2025] [Indexed: 01/22/2025] Open
Abstract
Deer antlers are the only mammalian appendages that can fully regenerate from periosteum of pedicles (PP). This regeneration process starts from regenerative healing of wounds. Removal of PP abolishes antler regeneration, however, the regenerative cutaneous wound healing proceeds, indicating that some factors in the circulation contribute to this healing. In this study, we produced a wound in the scalp of deer either in antler regeneration period (ARP) (n = 3) or in non-ARP (n = 3). Results showed full regeneration took place only when the wound was created during ARP. Interestingly, topical application of systemic factors from ARP (n = 9) promoted regenerative wound healing in rats. Comparative proteomics analysis (n = 3) revealed that PRG4 and IGF-1 were high during ARP, and topical application of PRG4 + IGF-1 promoted restoration in rat FTE wounds. We believe that, ultimately, incorporating systemic factors into advanced wound care modalities could offer new opportunities for regenerative healing in the clinical setting.
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Affiliation(s)
- Qianqian Guo
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, Jilin, China
| | - Guokun Zhang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China
| | - Jing Ren
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China
| | - Jiping Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China
| | - Zhen Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China
| | - Hengxing Ba
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China
| | - Zihao Ye
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China
| | - Ying Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Junjun Zheng
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, Jilin, China.
| | - Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China.
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Alibardi L. Regeneration, Regengrow and Tissue Repair in Animals: Evolution Indicates That No Regeneration Occurs in Terrestrial Environments but Only Recovery Healing. J Dev Biol 2024; 13:2. [PMID: 39846631 PMCID: PMC11755470 DOI: 10.3390/jdb13010002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 12/16/2024] [Accepted: 12/25/2024] [Indexed: 01/24/2025] Open
Abstract
The present, brief review paper summarizes previous studies on a new interpretation of the presence and absence of regeneration in invertebrates and vertebrates. Broad regeneration is considered exclusive of aquatic or amphibious animals with larval stages and metamorphosis, where also a patterning process is activated for whole-body regeneration or for epimorphosis. In contrast, terrestrial invertebrates and vertebrates can only repair injury or the loss of body parts through a variable "recovery healing" of tissues, regengrow or scarring. This loss of regeneration likely derives from the change in genomes during land adaptation, which included the elimination of larval stages and intense metamorphosis. The terrestrial conditions are incompatible with the formation of embryonic organs that are necessary for broad regeneration. In fact, no embryonic organ can survive desiccation, intense UV or ROS exposition on land, and rapid reparative processes without embryonic patterning, such as recovery healing and scarring, have replaced broad regeneration in terrestrial species. The loss of regeneration in land animals likely depends on the alteration of developmental gene pathways sustaining regeneration that occurred in progenitor marine animals. Terrestrial larval stages, like those present in insects among arthropods, only metamorphose using small body regions indicated as imaginal disks, a terrestrial adaptation, not from a large restructuring process like in aquatic-related animals. These invertebrates can reform body appendages only during molting, a process indicated as regengrow, not regeneration. Most amniotes only repair injuries through scarring or a variable recovery healing, occasionally through regengrow, the contemporaneous healing in conjunction with somatic growth, forming sometimes new heteromorphic organs.
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Meng D, Li Y, Chen Z, Guo J, Yang M, Peng Y. Exosomes Derived from Antler Mesenchymal Stem Cells Promote Wound Healing by miR-21-5p/STAT3 Axis. Int J Nanomedicine 2024; 19:11257-11273. [PMID: 39524924 PMCID: PMC11546281 DOI: 10.2147/ijn.s481044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024] Open
Abstract
Background Deer antlers, unique among mammalian organs for their ability to regenerate annually without scar formation, provide an innovative model for regenerative medicine. This study explored the potential of exosomes derived from antler mesenchymal stem cells (AMSC-Exo) to enhance skin wound healing. Methods We explored the proliferation, migration and angiogenesis effects of AMSC-Exo on HaCaT cells and HUVEC cells. To investigate the skin repairing effect of AMSC-Exo, we established a full-thickness skin injury mouse model. Then the skin thickness, the epidermis, collagen fibers, CD31 and collagen expressions were tested by H&E staining, Masson's trichrome staining and immunofluorescence experiments. MiRNA omics analysis was conducted to explore the mechanism of AMSC-Exo in skin repairing. Results AMSC-Exo stimulated the proliferation and migration of HaCaT cells, accelerated the migration and angiogenesis of HUVEC cells. In the mouse skin injury model, AMSC-Exo stimulated angiogenesis and regulated the extracellular matrix by facilitating the conversion of collagen type III to collagen type I, restoring epidermal thickness to normal state without aberrant hyperplasia. Notably, AMSC-Exo enhanced the quality of wound healing with increased vascularization and reduced scar formation. MiRNAs in AMSC-Exo, especially through the miR-21-5p/STAT3 signaling pathway, played a crucial role in these processes. Conclusion This study underscores the efficacy of AMSC-Exo in treating skin wounds, suggesting a new approach for enhancing skin repair and regeneration.
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Affiliation(s)
- Deshuang Meng
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, Jilin, 130112, People’s Republic of China
| | - Yingrui Li
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, Jilin, 130112, People’s Republic of China
| | - Ze Chen
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, Jilin, 130112, People’s Republic of China
| | - Jia Guo
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, Jilin, 130112, People’s Republic of China
| | - Min Yang
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, Jilin, 130112, People’s Republic of China
| | - Yinghua Peng
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, Jilin, 130112, People’s Republic of China
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Chen Z, Meng D, Pang X, Guo J, Li T, Song J, Peng Y. Deer antler stem cells immortalization by modulation of hTERT and the small extracellular vesicles characters. Front Vet Sci 2024; 11:1440855. [PMID: 39430380 PMCID: PMC11486761 DOI: 10.3389/fvets.2024.1440855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 09/12/2024] [Indexed: 10/22/2024] Open
Abstract
Background Deer antler stem cells (AnSCs) exhibit properties of both embryonic and mesenchymal stem cells, with superior self-renewal and proliferation, which drive rapid antler growth and regeneration. AnSCs and their derived small extracellular vesicles (sEVs) hold promising potential for applications in regeneration medicine. Due to the restricted proliferative capacity inherent in primary cells, the production capacity of AnSCs and their sEVs are limited. Human telomerase reverse transcriptase (hTERT) is the most important telomerase subunit, hTERT gene insertion has been successfully employed in generating immortalized cell lines. Results In this study, we successfully established immortalized AnSCs by transducing the hTERT gene using lentivirus. Compared to primary AnSCs, hTERT-AnSCs demonstrated extended passage potential and accelerated proliferation rates while maintaining the mesenchymal stem cell surface markers CD44 and CD90. Additionally, hTERT-AnSCs retained the capacity for osteogenic, adipogenic, and chondrogenic differentiation. sEVs derived from hTERT-AnSCs exhibited a particle size distribution similar to that of AnSCs, both displaying a cup-shaped morphology and expressing CD81, ALIX, and TSG101, while notably lacking GM130 expression. Conclusion We successfully isolated primary stem cells from deer antler and established the immortalized hTERT-AnSCs. Remarkably, this cell line maintains its stem cell characteristics even after 40 passages. The sEVs derived from these cells exhibit identical morphological and structural features to those of primary AnSCs. This research provides essential technical support for the application of AnSCs and their sEVs in regenerative medicine.
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Affiliation(s)
- Ze Chen
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Deshuang Meng
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Xin Pang
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
- School of Chemistry and Life Science, Changchun University of Technology, Changchun, China
| | - Jia Guo
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Tiejun Li
- Dongfeng Sika Deer Industry Development Service Center, Dongfeng, China
| | - Jun Song
- Dongfeng Sika Deer Industry Development Service Center, Dongfeng, China
| | - Yinghua Peng
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
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Hu P, Zhang G, Ba H, Ren J, Li J, Wang Z, Li C. Reciprocal negative feedback between Prrx1 and miR-140-3p regulates rapid chondrogenesis in the regenerating antler. Cell Mol Biol Lett 2024; 29:56. [PMID: 38643083 PMCID: PMC11031908 DOI: 10.1186/s11658-024-00573-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 04/05/2024] [Indexed: 04/22/2024] Open
Abstract
During growth phase, antlers exhibit a very rapid rate of chondrogenesis. The antler is formed from its growth center reserve mesenchyme (RM) cells, which have been found to be the derivatives of paired related homeobox 1 (Prrx1)-positive periosteal cells. However, the underlying mechanism that drives rapid chondrogenesis is not known. Herein, the miRNA expression profiles and chromatin states of three tissue layers (RM, precartilage, and cartilage) at different stages of differentiation within the antler growth center were analyzed by RNA-sequencing and ATAC-sequencing. We found that miR-140-3p was the miRNA that exhibited the greatest degree of upregulation in the rapidly growing antler, increasing from the RM to the cartilage layer. We also showed that Prrx1 was a key upstream regulator of miR-140-3p, which firmly confirmed by Prrx1 CUT&Tag sequencing of RM cells. Through multiple approaches (three-dimensional chondrogenic culture and xenogeneic antler model), we demonstrated that Prrx1 and miR-140-3p functioned as reciprocal negative feedback in the antler growth center, and downregulating PRRX1/upregulating miR-140-3p promoted rapid chondrogenesis of RM cells and xenogeneic antler. Thus, we conclude that the reciprocal negative feedback between Prrx1 and miR-140-3p is essential for balancing mesenchymal proliferation and chondrogenic differentiation in the regenerating antler. We further propose that the mechanism underlying chondrogenesis in the regenerating antler would provide a reference for helping understand the regulation of human cartilage regeneration and repair.
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Affiliation(s)
- Pengfei Hu
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China.
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China.
| | - Guokun Zhang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Hengxing Ba
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Jing Ren
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Jiping Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Zhen Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China.
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Li C, Li Y, Wang W, Scimeca M, Melino G, Du R, Shi Y. Deer antlers: the fastest growing tissue with least cancer occurrence. Cell Death Differ 2023; 30:2452-2461. [PMID: 37864097 PMCID: PMC10733395 DOI: 10.1038/s41418-023-01231-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 09/20/2023] [Accepted: 10/02/2023] [Indexed: 10/22/2023] Open
Abstract
Deer antlers are a bony organ solely able to acquired distinct unique attributes during evolution and all these attributes are against thus far known natural rules. One of them is as the fastest animal growing tissue (2 cm/day), they are remarkably cancer-free, despite high cell division rate. Although tumor-like nodules on the long-lived castrate antlers in some deer species do occur, but they are truly benign in nature. In this review, we tried to find the answer to this seemingly contradictory phenomenon based on the currently available information and give insights into possible clinic application. The antler growth center is located in its tip; the most intensive dividing cells are resident in the inner layer of reserve mesenchyme (RM), and these cells are more adopted to osteosarcoma rather than to normal bone tissues in gene expression profiles but acquire their energy mainly through aerobic oxidative phosphorylation pathway. To counteract propensity of neoplastic transformation, antlers evolved highly efficient apoptosis exactly in the RM, unparalleled by any known tissues; and annual wholesale cast to jettison the corps. Besides, some strong cancer suppressive genes including p53 cofactor genes and p53 regulator genes are highly positively selected by deer, which would have certainly contributed to curb tumorigenesis. Thus far, antler extracts and RM cells/exosomes have been tried on different cancer models either in vitro or in vivo, and all achieved positive results. These positive experimental results together with the anecdotal folklore that regular consumption of velvet antler is living with cancer-free would encourage us to test antlers in clinic settings.
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Affiliation(s)
- Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Yan Li
- College of Veterinary Medicine, Hebei Agricultural University, Baoding, China
| | - Wenying Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Manuel Scimeca
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Gerry Melino
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy.
| | - Rui Du
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, China.
| | - Yufang Shi
- The Third Affiliated Hospital of Soochow University/The First People's Hospital of Changzhou, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Suzhou Medical College of Soochow University, Suzhou, China.
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Li J, Wang D, Ren J, Wang Y, Hu P, Li C. A simple method for effective cryopreservation of antlerogenic periosteum of sika deer. JOURNAL OF EXPERIMENTAL ZOOLOGY. PART A, ECOLOGICAL AND INTEGRATIVE PHYSIOLOGY 2023; 339:1017-1025. [PMID: 37635631 DOI: 10.1002/jez.2750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2023] [Revised: 08/13/2023] [Accepted: 08/16/2023] [Indexed: 08/29/2023]
Abstract
Antlerogenic periosteum (AP) is the unique tissue type that gives rise to antlers and their antecedents, the pedicles. Deer antlers are the only mammalian organ that can fully regenerate. Efficient investigation of the mechanism of antler formation and regeneration requires year-round availability of AP, but naturally AP can only be obtained less than two months in a year. In the present study we took the cryopreservation approach to store the sampled AP in ultra-low temperature to overcome the limited period of availability. First, we evaluated the suitability of vitrification and cell cryopreservation method for cryopreservation of AP, cell migration status of the AP tissue pieces confirmed that vitrification methods did not work as the only few AP cells migrated out, whereas migrated cell numbers in the cell-cryo group (conventional method for cryopreservation of cells) were comparable to those of the fresh AP group. To further evaluate the suitability of cell cryopreservation method for AP tissue, AP samples were allocated into three groups based on the different ratios of cryopreservation reagents (dimethyl sulfoxide [DMSO], dulbecco's modified eagle's medium [DMEM] and fetal bovine serum [FBS]): AP-Cell-1 (1:4:5), AP-Cell-2 (1:2:7) and AP-Cell-3 (1:0:9), the results showed that migrated cell number were again comparable to the fresh AP group. There was no significant difference between the cell-cryo groups (AP-Cell-1 and AP-Cell-3) and the fresh group: (1) in viability (p > 0.05) through trypan blue staining (91.2%, 90.8%, and 92.4%, respectively); (2) in the attachment day, and all on Day 5 after cell seeding; (3) in cell proliferation rate (p > 0.05) through Cell Counting kit 8 (CCK8) measurement; and (4) in number of the formed clones (Clonogenicity). In the in vivo trials, there was no visible difference in temporal differentiation sequence of the formed xenogeneic antlers between the fresh AP and cryopreserved AP (AP-Cell-1 and AP-Cell-3). Overall, we found that the AP tissue was well cryopreserved just using the conventional freezing and thawing methods for cells, and their viability and developmental potential comparable to the fresh AP both in vitro and in vivo. The long-term preservation of the AP tissue is of great significance for the study of the periosteum biology in general and the mechanism underlying xenogeneic generation and regeneration of deer antlers in specific.
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Affiliation(s)
- Jiping Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Dongxu Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Jing Ren
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Yusu Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Pengfei Hu
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
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Zhang G, Wang D, Ren J, Li J, Guo Q, Shi L, Li C. Antler stem cell-derived exosomes promote regenerative wound healing via fibroblast-to-myofibroblast transition inhibition. J Biol Eng 2023; 17:67. [PMID: 37940994 PMCID: PMC10633995 DOI: 10.1186/s13036-023-00386-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Accepted: 10/23/2023] [Indexed: 11/10/2023] Open
Abstract
INTRODUCTION The typical outcome of mammalian wound healing is scarring, a fibrotic process mediated by myofibroblast aggregation. Perfect healing in a clinical setting is relatively unexplored. Surprisingly, our previous studies have shown that the large wound (10 cm diameter or more) of the pedicle of deer naturally achieves regenerative restoration, realized through a paracrine pathway from adjacent antler stem cells (AnSCs). METHODS AnSC-derived exosomes (AnSC-exos) were topically injected around the full-thickness wounds in a rat model. The effects on the rate of wound healing and the quality of healing were evaluated via morphological, histological, and molecular biological techniques on days 14 and 28 after surgery. RESULTS The results showed that AnSC-exos significantly accelerated the rate of wound healing and improved healing quality, including regeneration of cutaneous appendages (hair follicles and sebaceous glands) and the distribution pattern of collagen (basket-weave-like) in the healed skin. These effects of AnSC-exos were comparable to those of AnSCs but were significantly more potent than those of exosomes derived from bone marrow mesenchymal stem cells (bMSC-exos). Furthermore, AnSC-exos treatment effectively inhibited fibroblast-to-myofibroblast transition (FMT), as evidenced by the reduction of full-thickness skin injury-induced FMT in vivo and TGF-β1-induced FMT in vitro. CONCLUSION AnSC-exos could effectively promote regenerative cutaneous wound healing, highly likely through FMT inhibition. This suggests that AnSC-exos treatment could provide the potential for a novel approach to induce regenerative wound healing in the clinical setting.
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Affiliation(s)
- Guokun Zhang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, No. 1345 of Pudong Rd., Changchun, Jilin, 130600, China
| | - Dongxu Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, No. 1345 of Pudong Rd., Changchun, Jilin, 130600, China
| | - Jing Ren
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, No. 1345 of Pudong Rd., Changchun, Jilin, 130600, China
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China
| | - Jiping Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, No. 1345 of Pudong Rd., Changchun, Jilin, 130600, China
| | - Qianqian Guo
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, No. 1345 of Pudong Rd., Changchun, Jilin, 130600, China
| | - Liyan Shi
- China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, No. 1345 of Pudong Rd., Changchun, Jilin, 130600, China.
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China.
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Zhang G, Shi L, Li J, Wang S, Ren J, Wang D, Hu P, Wang Y, Li C. Antler stem cell exosomes alleviate pulmonary fibrosis via inhibiting recruitment of monocyte macrophage, rather than polarization of M2 macrophages in mice. Cell Death Discov 2023; 9:359. [PMID: 37770458 PMCID: PMC10539297 DOI: 10.1038/s41420-023-01659-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 09/11/2023] [Accepted: 09/19/2023] [Indexed: 09/30/2023] Open
Abstract
Pulmonary fibrosis (PF), a chronic interstitial lung disease, is characterized by over-abundant deposition of extracellular matrix consisting mainly of collagen I. In previous studies, we demonstrated that deer antler stem cells (AnSCs), a novel type of adult stem cell, are capable of significantly down-regulating collagen formation in different organs and tissues and speculated that they could effectively treat PF via reducing collagen deposition in the lung tissue. In the present study, we found that administration of AnSCs improved the survival rate of PF mice and reduced lung fibrosis, collagen deposition and myofibroblast differentiation. The effects of AnSC treatment were significantly better than the positive control (adipose-derived stem cells). Interestingly, AnSC-Exos were almost equally effective as AnSCs in treating PF, suggesting that the effects of AnSCs on reduction of PF may be mainly through a paracrine mechanism. Further, AnSC-Exos reduced the number of M2 macrophages, a type of macrophage that secrets pro-fibrotic factors to accelerate fibrotic progression, in the lung tissues. In vitro experiments showed that the effects of AnSC-Exos on macrophage modulation were likely achieved via inhibition of the recruitment of circulating monocyte-derived macrophages (reducing the number of macrophages), rather than via inhibition of M2 polarization of macrophages. Inhibition of macrophage recruitment by AnSCs may be achieved indirectly via inhibiting CCL7 expression in fibroblasts; both let-7b and let-7a were highly enriched in AnSC-Exos and may play a critical role in the inhibition of CCL7 expression of fibroblasts. Collectively, the use of antler stem cells or their exosomes opens up a novel strategy for PF treatment in the clinical setting.
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Affiliation(s)
- Guokun Zhang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 130600, Changchun, China
| | - Liyan Shi
- China-Japan Union Hospital, Jilin University, 130033, Changchun, China
| | - Jiping Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 130600, Changchun, China
| | - Shengnan Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 130600, Changchun, China
| | - Jing Ren
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 130600, Changchun, China
- College of Chinese Medicinal Materials, Jilin Agricultural University, 130118, Changchun, China
| | - Dongxu Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 130600, Changchun, China
| | - Pengfei Hu
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 130600, Changchun, China
| | - Yimin Wang
- China-Japan Union Hospital, Jilin University, 130033, Changchun, China
| | - Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, 130600, Changchun, China.
- College of Chinese Medicinal Materials, Jilin Agricultural University, 130118, Changchun, China.
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11
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Liu Q, Li J, Chang J, Guo Y, Wen D. The characteristics and medical applications of antler stem cells. Stem Cell Res Ther 2023; 14:225. [PMID: 37649124 PMCID: PMC10468909 DOI: 10.1186/s13287-023-03456-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 08/17/2023] [Indexed: 09/01/2023] Open
Abstract
Antlers are the only fully regenerable mammalian appendages whose annual renewal is initiated by antler stem cells (ASCs), defined as a specialized type of mesenchymal stem cells (MSCs) with embryonic stem cell properties. ASCs possess the same biological features as MSCs, including the capacity for self-renewal and multidirectional differentiation, immunomodulatory functions, and the maintenance of stem cell characteristics after multiple passages. Several preclinical studies have shown that ASCs exhibit promising potential in wound healing, bone repair, osteoarthritis, anti-tissue fibrosis, anti-aging, and hair regeneration. Medical applications based on ASCs and ASC-derived molecules provide a new source of stem cells and therapeutic modalities for regenerative medicine. This review begins with a brief description of antler regeneration and the role of ASCs. Then, the properties and advantages of ASCs are described. Finally, medical research advances regarding ASCs are summarized, and the prospects and challenges of ASCs are highlighted.
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Affiliation(s)
- Qi Liu
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jiannan Li
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Jinghui Chang
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Yu Guo
- Department of Colorectal and Anal Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Dacheng Wen
- Department of Gastrointestinal Nutrition and Hernia Surgery, The Second Hospital of Jilin University, Changchun, Jilin, China.
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12
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Li C. Deer antler renewal gives insights into mammalian epimorphic regeneration. CELL REGENERATION (LONDON, ENGLAND) 2023; 12:26. [PMID: 37490254 PMCID: PMC10368610 DOI: 10.1186/s13619-023-00169-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 07/02/2023] [Indexed: 07/26/2023]
Abstract
Deer antlers are the only known mammalian organ that, once lost, can fully grow back naturally. Hence, the antler offers a unique opportunity to learn how nature has solved the problem of mammalian epimorphic regeneration (EpR). Comprehensive comparisons amongst different types of EpR reveal that antler renewal is fundamentally different from that in lower vertebrates such as regeneration of the newt limb. Surprisingly, antler renewal is comparable to wound healing over a stump of regeneration-incompetent digit/limb, bone fracture repair, and to a lesser extent to digit tip regeneration in mammals. Common to all these mammalian cases of reaction to the amputation/mechanical trauma is the response of the periosteal cells at the distal end/injury site with formation of a circumferential cartilaginous callus (CCC). Interestingly, whether the CCC can proceed to the next stage to transform to a blastema fully depends on the presence of an interactive partner. The actual form of the partner can vary in different cases with the nail organ in digit tip EpR, the opposing callus in bone fracture repair, and the closely associated enveloping skin in antler regeneration. Due to absence of such an interactive partner, the CCC of a mouse/rat digit/limb stump becomes involuted gradually. Based on these discoveries, we created an interactive partner for the rat digit/limb stump through surgically removal of the interposing layers of loose connective tissue and muscle between the resultant CCC and the enveloping skin after amputation and by forcefully bonding two tissue types tightly together. In so doing partial regeneration of the limb stump occurred. In summary, if EpR in humans is to be realized, then I envisage that it would be more likely in a manner akin to antler regeneration rather to that of lower vertebrates such as newt limbs.
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Affiliation(s)
- Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, 130600, China.
- Jilin Provincial Key Laboratory of Deer Antler Biology, Changchun, 130600, China.
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130000, China.
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13
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Qin T, Zhang G, Zheng Y, Li S, Yuan Y, Li Q, Hu M, Si H, Wei G, Gao X, Cui X, Xia B, Ren J, Wang K, Ba H, Liu Z, Heller R, Li Z, Wang W, Huang J, Li C, Qiu Q. A population of stem cells with strong regenerative potential discovered in deer antlers. Science 2023; 379:840-847. [PMID: 36821675 DOI: 10.1126/science.add0488] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Accepted: 01/10/2023] [Indexed: 02/25/2023]
Abstract
The annual regrowth of deer antlers provides a valuable model for studying organ regeneration in mammals. We describe a single-cell atlas of antler regrowth. The earliest-stage antler initiators were mesenchymal cells that express the paired related homeobox 1 gene (PRRX1+ mesenchymal cells). We also identified a population of "antler blastema progenitor cells" (ABPCs) that developed from the PRRX1+ mesenchymal cells and directed the antler regeneration process. Cross-species comparisons identified ABPCs in several mammalian blastema. In vivo and in vitro ABPCs displayed strong self-renewal ability and could generate osteochondral lineage cells. Last, we observed a spatially well-structured pattern of cellular and gene expression in antler growth center during the peak growth stage, revealing the cellular mechanisms involved in rapid antler elongation.
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Affiliation(s)
- Tao Qin
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Guokun Zhang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Yi Zheng
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Shengyou Li
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Yuan Yuan
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Qingjie Li
- Research Center of Traditional Chinese Medicine, The Affiliated Hospital to Changchun University of Chinese Medicine, Changchun 130021, China
| | - Mingliang Hu
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Huazhe Si
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Guanning Wei
- School of Life Sciences, Jilin University, Changchun 130012, Jilin, China
| | - Xueli Gao
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Xinxin Cui
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Bing Xia
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Jing Ren
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Kun Wang
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
| | - Hengxing Ba
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Zhen Liu
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
| | - Rasmus Heller
- Section for Computational and RNA Biology, Department of Biology, University of Copenhagen, N 2200 Copenhagen, Denmark
| | - Zhipeng Li
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Wen Wang
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
- Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming 650223, China
| | - Jinghui Huang
- Department of Orthopaedics, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
| | - Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
- College of Traditional Chinese Medicine, Jilin Agricultural University, Changchun, China
| | - Qiang Qiu
- School of Ecology and Environment, Northwestern Polytechnical University, Xi'an 710072, China
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14
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Ba H, Wang X, Wang D, Ren J, Wang Z, Sun HX, Hu P, Zhang G, Wang S, Ma C, Wang Y, Wang E, Chen L, Liu T, Gu Y, Li C. Single-cell transcriptome reveals core cell populations and androgen-RXFP2 axis involved in deer antler full regeneration. CELL REGENERATION (LONDON, ENGLAND) 2022; 11:43. [PMID: 36542206 PMCID: PMC9772379 DOI: 10.1186/s13619-022-00153-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 11/11/2022] [Indexed: 12/24/2022]
Abstract
Deer antlers constitute a unique mammalian model for the study of both organ formation in postnatal life and annual full regeneration. Previous studies revealed that these events are achieved through the proliferation and differentiation of antlerogenic periosteum (AP) cells and pedicle periosteum (PP) cells, respectively. As the cells resident in the AP and the PP possess stem cell attributes, both antler generation and regeneration are stem cell-based processes. However, the cell composition of each tissue type and molecular events underlying antler development remain poorly characterized. Here, we took the approach of single-cell RNA sequencing (scRNA-Seq) and identified eight cell types (mainly THY1+ cells, progenitor cells, and osteochondroblasts) and three core subclusters of the THY1+ cells (SC2, SC3, and SC4). Endothelial and mural cells each are heterogeneous at transcriptional level. It was the proliferation of progenitor, mural, and endothelial cells in the activated antler-lineage-specific tissues that drove the rapid formation of the antler. We detected the differences in the initial differentiation process between antler generation and regeneration using pseudotime trajectory analysis. These may be due to the difference in the degree of stemness of the AP-THY1+ and PP-THY1+ cells. We further found that androgen-RXFP2 axis may be involved in triggering initial antler full regeneration. Fully deciphering the cell composition for these antler tissue types will open up new avenues for elucidating the mechanism underlying antler full renewal in specific and regenerative medicine in general.
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Affiliation(s)
- Hengxing Ba
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, 130600 China
- Jilin Provincial Key Laboratory of Deer Antler Biology, Changchun, 130600 China
| | - Xin Wang
- BGI-Shenzhen, Shenzhen, 518083 Guangdong China
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, RNA Institute, Wuhan University, Wuhan, China
| | - Datao Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, 130600 China
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, 130112, Changchun, China
| | - Jing Ren
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, 130600 China
- Jilin Provincial Key Laboratory of Deer Antler Biology, Changchun, 130600 China
| | - Zhen Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, 130600 China
- Jilin Provincial Key Laboratory of Deer Antler Biology, Changchun, 130600 China
| | - Hai-Xi Sun
- BGI-Shenzhen, Shenzhen, 518083 Guangdong China
| | - Pengfei Hu
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, 130600 China
- Jilin Provincial Key Laboratory of Deer Antler Biology, Changchun, 130600 China
| | - Guokun Zhang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, 130600 China
- Jilin Provincial Key Laboratory of Deer Antler Biology, Changchun, 130600 China
| | - Shengnan Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, 130600 China
- Jilin Provincial Key Laboratory of Deer Antler Biology, Changchun, 130600 China
| | - Chao Ma
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, 130600 China
- Jilin Provincial Key Laboratory of Deer Antler Biology, Changchun, 130600 China
| | - Yusu Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, 130600 China
- Jilin Provincial Key Laboratory of Deer Antler Biology, Changchun, 130600 China
| | - Enpeng Wang
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130117 China
| | - Liang Chen
- Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, RNA Institute, Wuhan University, Wuhan, China
| | - Tianbin Liu
- BGI-Shenzhen, Shenzhen, 518083 Guangdong China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049 China
| | - Ying Gu
- BGI-Shenzhen, Shenzhen, 518083 Guangdong China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049 China
- Guangdong Provincial Key Laboratory of Genome Read and Write, BGI-Shenzhen, Shenzhen, 518120 Guangdong China
| | - Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, 130600 China
- Jilin Provincial Key Laboratory of Deer Antler Biology, Changchun, 130600 China
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118 China
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15
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Han R, Han L, Xia Y, Guo M, Li H. lncRNA Sequencing of Antler Mesenchymal Tissue Revealed that the Regulatory Network of Antler Cell Proliferation and Differentiation. Anim Biotechnol 2022; 33:1629-1638. [PMID: 34010106 DOI: 10.1080/10495398.2021.1924762] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Antlers have been widely studied due to their unique physiological characteristics, such as rapid growth, periodic shedding and regeneration. However, little is known about how antler growth is regulated by long non-coding RNA (lncRNA). The aim of the present study was to identify the lncRNAs expression profile and explore the function of lncRNAs during the antler growth. Herein, RNA-sequencing technology (RNA-seq) was performed on the three growth periods (early developmental period: EP, middle developmental period: MP, later developmental period: LP) of male sika deer (Cervus nippon) antler, 16 differentially expressed lncRNAs (DE lncRNAs) and 11 DE lncRNAs were identified in EP vs MP and MP vs LP related to cell proliferation and cell differentiation, respectively. Finally, lncRNAs-mRNAs co-expression networks were constructed based on the identified DE lncRNAs and their potential trans-target genes. The result reveals that lncRNAs may play diverse roles in different periods of antler growth. It provides a novel perspective for revealing the molecular mechanism of antler growth.
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Affiliation(s)
- Ruobing Han
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, China
| | - Lei Han
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, China
| | - Yanling Xia
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, China
| | - Mengya Guo
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, China
| | - Heping Li
- College of Wildlife and Protected Area, Northeast Forestry University, Harbin, China
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16
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Hu P, Wang Z, Li J, Wang D, Wang Y, Zhao Q, Li C. Identification and Characterization of Alternative Splicing Variants and Positive Selection Genes Related to Distinct Growth Rates of Antlers Using Comparative Transcriptome Sequencing. Animals (Basel) 2022; 12:2203. [PMID: 36077923 PMCID: PMC9454627 DOI: 10.3390/ani12172203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 08/19/2022] [Accepted: 08/23/2022] [Indexed: 11/16/2022] Open
Abstract
The molecular mechanism underlying rapid antler growth has not been elucidated. The contrast of the wapiti and sika deer antler provides a potential model for comparative studies for the identification of potent growth factors and unique regulatory systems. In the present study, reference transcriptomes of antler RM tissue of wapiti and sika deer were constructed using single molecule real time sequencing data. The expression profiling, positive selection, and alternative splicing of the antler transcripts were compared. The results showed that: a total of 44,485 reference full-length transcripts of antlers were obtained; 254 highly expressed transcripts (HETs) and 1936 differentially expressed genes (DEGs) were enriched and correlated principally with translation, endochondral ossification and ribosome; 228 genes were found to be under strong positive selection and would thus be important for the evolution of wapiti and sika deer; among the alternative splicing variants, 381 genes were annotated; and 4 genes with node degree values greater than 50 were identified through interaction network analysis. We identified a negative and a positive regulator for rapid antler growth, namely RNA Binding Motif Protein X-Linked (RBMX) and methyltransferase-like 3 (METTL3), respectively. Overall, we took advantage of this significant difference in growth rate and performed the comparative analyses of the antlers to identify key specific factors that might be candidates for the positive or negative regulation of phenomenal antler growth rate.
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Affiliation(s)
- Pengfei Hu
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun 130600, China
| | - Zhen Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun 130600, China
| | - Jiping Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun 130600, China
| | - Dongxu Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun 130600, China
| | - Yusu Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun 130600, China
| | - Quanmin Zhao
- College of Traditional Chinese Medicine, Jilin Agricultural University, Changchun 130118, China
| | - Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun 130600, China
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17
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Wang Y, Hu W. Progress of Noncoding RNA Regulating the Growth and Development of Antler Tissue Research. BIOMED RESEARCH INTERNATIONAL 2022; 2022:3541577. [PMID: 35909491 PMCID: PMC9325626 DOI: 10.1155/2022/3541577] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 06/28/2022] [Accepted: 07/12/2022] [Indexed: 11/17/2022]
Abstract
Antler is the secondary sexual characteristic of deer, which develops on the forehead at puberty. It is the only organ that can be regenerated entirely in mammals. Therefore, it is often used as a research model in the field of organ regeneration and wound repair. Many growth factors and proteins play an active role throughout the developmental process of antler regeneration. With the rapid development of sequencing technology, more and more noncoding RNAs (ncRNAs) have been discovered, and the relationship between ncRNA and antler regeneration has gradually become clear. This paper focuses on the research progress of several ncRNAs (including miRNA and lncRNA) in deer antler tissues, which are helpful to reveal the molecular mechanism of deer antler regeneration at the molecular level.
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Affiliation(s)
- Yipu Wang
- Biochemistry and Molecular Biology, Jilin Agricultural University, Changchun City, Jilin Province 130000, China
| | - Wei Hu
- Biochemistry and Molecular Biology, Jilin Agricultural University, Changchun City, Jilin Province 130000, China
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18
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Guo Q, Zheng J, Ba H, Sun H, Zhai J, Wang W, Li C. Calreticulin Identified as One of the Androgen Response Genes That Trigger Full Regeneration of the Only Capable Mammalian Organ, the Deer Antler. Front Cell Dev Biol 2022; 10:862841. [PMID: 35769266 PMCID: PMC9235033 DOI: 10.3389/fcell.2022.862841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 04/22/2022] [Indexed: 11/13/2022] Open
Abstract
Deer antlers are male secondary sexual characters that develop to become bone; they are unique appendages that, once lost, can fully regenerate from the permanent bony protuberances or pedicles. Pedicle periosteum (PP) is the tissue that gives rise to the regenerating antlers with three differentiation stages, namely, dormant (DoPP), potentiated (PoPP), and activated (AcPP). Thus far, the transition from the PoPP to the AcPP has not been studied. Our results showed that the AcPP cells maintained their original stem cell features by expressing mesenchymal stem cell (MSC) markers CD73, CD90, and CD105, although they had entered the proliferation mode. The differentially expressed genes (DEGs) in the AcPP compared with those of the PoPP were mainly involved in protein processing, cell cycle, and calcium signaling pathways. Calreticulin (CALR), an androgen response gene, was significantly differentially upregulated in the AcPP cells, and its expression level was negatively regulated by androgens, in contrast to the currently known model systems where all regulation is positive. The downregulation of CALR expression in the AcPP cells in vitro inhibited cell proliferation, induced apoptosis, and inhibited cell cycle progression at G1-S transition. Therefore, CALR is likely a downstream mediator of androgen hormones for triggering initiation of antler regeneration. We believe that the identification of CALR has not only discovered "one critical piece" of the "jigsaw puzzle" in the initiation of antler regeneration but also helps in revealing the mechanism underlying this unique mammalian epimorphic regeneration and has also opened a new avenue for the study of the nature of CALR regulation by androgen (putative binding partners), thus facilitating the identification of potential molecule(s) for investigation as targets for clinical evaluation.
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Affiliation(s)
- Qianqian Guo
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Jilin, China
- Institute of Special Economic Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Jilin, China
| | - Junjun Zheng
- Institute of Special Economic Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Jilin, China
| | - Hengxing Ba
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Jilin, China
| | - Hongmei Sun
- Institute of Special Economic Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Jilin, China
| | - Jingjie Zhai
- Department of Oral Implantology, Jilin Provincial Key Laboratory of Sciences and Technology for Stomatology Nanoengineering, Hospital of Stomatology, Jilin University, Jilin, China
| | - Wenying Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Jilin, China
| | - Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Jilin, China
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19
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Zhang G, Wang D, Ren J, Sun H, Li J, Wang S, Shi L, Wang Z, Yao M, Zhao H, Li C. Velvet Antler Peptides Reduce Scarring via Inhibiting the TGF-β Signaling Pathway During Wound Healing. Front Med (Lausanne) 2022; 8:799789. [PMID: 35127757 PMCID: PMC8814364 DOI: 10.3389/fmed.2021.799789] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 12/30/2021] [Indexed: 12/21/2022] Open
Abstract
AIM Scar formation generally occurs in cutaneous wound healing in mammals, mainly caused by myofibroblast aggregations, and currently with few effective treatment options. However, the pedicle wound (about 10 cm in diameter) of the deer can initiate regenerative healing, which has been found to be achieved via paracrine factors from the internal tissues of antlers. METHODS Enzymatically digested velvet antler peptides (EVAP) were prepared along with other types of antler extracts as the controls. The effects of EVAP on healing of full-thickness skin wounds were evaluated using rats in vivo, and on myofibroblast transdifferentiation tested using transforming growth factor-β1 (TGF-β1)-induced human dermal fibroblasts in vitro. RESULTS EVAP significantly accelerated the wound healing rate, reduced scar formation, and improved the healing quality, including promoted angiogenesis, increased number of skin appendages (hair follicles and sebaceous glands) and improved the distribution pattern of collagen fibers (basket-wave like) in the healed tissue. Moreover, EVAP significantly down-regulated the expression levels of genes pro- scar formation (Col1a2 and TGF-β1), and up-regulated the expression levels of genes anti-scar formation (Col3a1 and TGF-β3), and suppressed the excessive transdifferentiation of myofibroblasts and the formation of collagen I in vivo and in vitro. Furthermore, we found these effects were highly likely achieved by inhibiting the TGF-β signaling pathway, evidenced by decreased expression levels of the related genes, including TGF-β1, Smad2, p-Smad2, α-SMA, and collagen I. CONCLUSIONS EVAP may be a promising candidate to be developed as a clinic drug for regenerative wound healing.
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Affiliation(s)
- Guokun Zhang
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences (CAAS), Changchun, China
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
- Jilin Academy of Sika Deer Industry, Changchun, China
- Key Laboratory of Antler Biology of Jilin, Changchun, China
| | - Dongxu Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
- Key Laboratory of Antler Biology of Jilin, Changchun, China
| | - Jing Ren
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
- Key Laboratory of Antler Biology of Jilin, Changchun, China
| | - Hongmei Sun
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences (CAAS), Changchun, China
| | - Jiping Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
- Key Laboratory of Antler Biology of Jilin, Changchun, China
| | - Shengnan Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
- Key Laboratory of Antler Biology of Jilin, Changchun, China
| | - Liyan Shi
- Department of Pathology, China-Japan Union Hospital, Jilin University, Changchun, China
| | - Zhen Wang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
- Key Laboratory of Antler Biology of Jilin, Changchun, China
| | - Mengjie Yao
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences (CAAS), Changchun, China
| | - Haiping Zhao
- College of Animal Science and Technology, Qingdao Agricultural University, Qingdao, China
| | - Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, China
- Jilin Academy of Sika Deer Industry, Changchun, China
- Key Laboratory of Antler Biology of Jilin, Changchun, China
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20
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Kierdorf U, Schultz M, Kierdorf H. The consequences of living longer-Effects of an experimentally extended velvet antler phase on the histomorphology of antler bone in fallow deer (Dama dama). J Anat 2021; 239:1104-1113. [PMID: 34169521 PMCID: PMC8546508 DOI: 10.1111/joa.13495] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 05/30/2021] [Accepted: 06/09/2021] [Indexed: 11/29/2022] Open
Abstract
Antlers are periodically regenerated paired cranial appendages of male deer (both sexes in reindeer) that constitute the fastest-growing bones in the animal kingdom. The annual antler cycle of male deer is linked to testicular activity and largely controlled by seasonal fluctuations of testosterone concentrations in their blood. We studied the effects of an experimental doubling (to eight months) of the velvet antler phase, during which the antlers are covered by skin (velvet), on the histomorphology of antler bone in three adult fallow bucks. Extension of the velvet antler phase in the experimental animals had been caused by administration of the antiandrogen cyproterone acetate (CPA). The distal portions of the antlers from two of the CPA-treated bucks exhibited partial sequestration of the antler cortex, with the separation plane typically located along the border between cortex and spongiosa. It is hypothesized that this was caused by cortical necrosis due to severe ischemia during later stages of the extended velvet antler phase. In places, new cancellous bone had been deposited on the resorption surface of the spongiosa, indicating a regeneration process. Normal fallow deer antlers ("controls") from this and a previous study, that is, antlers with a timespan of about four months between onset of new antler growth and velvet shedding, exhibited no or only minor bone remodeling and still contained remnants of calcified cartilage in their distal portions. In contrast, the antlers of the three CPA-treated bucks showed evidence (secondary osteons and resorption cavities) of marked bone remodeling along their entire length and lacked remnants of calcified cartilage. Our results underscore that the typical histological features of antler bone reflect its short-lived nature. Antlers are not mechanically loaded during the velvet stage, and it is presently unclear what triggered remodeling activity in the antlers whose lifespan had been experimentally extended.
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Affiliation(s)
- Uwe Kierdorf
- Department of BiologyUniversity of HildesheimHildesheimGermany
| | - Michael Schultz
- Department of BiologyUniversity of HildesheimHildesheimGermany
- Department of Anatomy and EmbryologyUniversity Medical CenterGöttingenGermany
| | - Horst Kierdorf
- Department of BiologyUniversity of HildesheimHildesheimGermany
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21
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Guo Q, Liu Z, Zheng J, Zhao H, Li C. Substances for regenerative wound healing during antler renewal stimulated scar-less restoration of rat cutaneous wounds. Cell Tissue Res 2021; 386:99-116. [PMID: 34390408 DOI: 10.1007/s00441-021-03505-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 07/07/2021] [Indexed: 10/20/2022]
Abstract
Scarification is the outcome of cutaneous wound healing under normal conditions. Although considerable effort has been expended in this field, scar-less healing has not been achieved satisfactorily. The lack of a good model of scar-free healing has contributed to this undesirable situation. However, the annual regeneration of deer antlers, which starts from regenerative wound healing over the top of the pedicles (permanent bony protuberances), may provide such a model. Therefore, in this study, we investigated the process of pedicle wound healing at the organ, tissue, cell, and molecular levels. Our results convincingly demonstrate that wounds over the pedicle preceded a regenerative healing process including regeneration of skin appendages, such as hair follicles. Compared to the scar healing in rats, regenerative healing of the pedicle wound exhibited a weaker inflammatory response, lack of myofibroblast induction, and higher ratios of Col III/Col I, TGF-β3/TGF-β1, and MMP/TIMP. Importantly, our periosteal transplantation experiments in vivo revealed that this regenerative healing process was achieved through induction of antler stem cells (ASCs). Further study showed that this effect of ASCs on regenerative healing was not species-specific but more generic and could be applied to other mammalian species, as injection of ASCs stimulated regenerative healing of full-thickness excisional cutaneous wounds in rats. Overall, our findings show that ASCs may have therapeutic potential in enhancing the quality of wound healing and preventing scar formation in clinical settings.
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Affiliation(s)
- Qianqian Guo
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences (CAAS), Changchun, Jilin, 130112, China
| | - Zhen Liu
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences (CAAS), Changchun, Jilin, 130112, China
| | - Junjun Zheng
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences (CAAS), Changchun, Jilin, 130112, China
| | - Haiping Zhao
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences (CAAS), Changchun, Jilin, 130112, China.
| | - Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, 130600, China.
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Zhang W, Ke CH, Guo HH, Xiao L. Antler stem cells and their potential in wound healing and bone regeneration. World J Stem Cells 2021; 13:1049-1057. [PMID: 34567424 PMCID: PMC8422928 DOI: 10.4252/wjsc.v13.i8.1049] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/10/2021] [Accepted: 07/27/2021] [Indexed: 02/06/2023] Open
Abstract
Compared to other vertebrates, the regenerative capacity of appendages in mammals is very limited. Deer antlers are an exception and can fully regenerate annually in postnatal mammals. This process is initiated by the antler stem cells (AnSCs). AnSCs can be divided into three types: (1) Antlerogenic periosteum cells (for initial pedicle and first antler formation); (2) Pedicle periosteum cells (for annual antler regeneration); and (3) Reserve mesenchyme cells (RMCs) (for rapid antler growth). Previous studies have demonstrated that AnSCs express both classic mesenchymal stem cells (MSCs) and embryonic stem cells (ESCs), and are able to differentiate into multiple cell types in vitro. Thus, AnSCs were defined as MSCs, but with partial ESC attributes. Near-perfect generative wound healing can naturally occur in deer, and wound healing can be achieved by the direct injection of AnSCs or topical application of conditioned medium of AnSCs in rats. In addition, in rabbits, the use of both implants with AnSCs and cell-free preparations derived from AnSCs can stimulate osteogenesis and repair defects of bone. A more comprehensive understanding of AnSCs will lay the foundation for developing an effective clinical therapy for wound healing and bone repair.
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Affiliation(s)
- Wei Zhang
- Medical Imaging Center, The First Affiliated Hospital of Jinan University, Jinan University, Guangzhou 510080, Guangdong Province, China
- Research & Development Center, YZ Health-tech Inc., Zhuhai 519000, Guangdong Province, China
| | - Chang-Hong Ke
- Research & Development Center, YZ Health-tech Inc., Zhuhai 519000, Guangdong Province, China
- School of Pharmacy, Jinan University, Guangzhou 510080, Guangdong Province, China
| | - Hai-Hua Guo
- Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, Guangdong Province, China
| | - Li Xiao
- Guangdong Laboratory Animals Monitoring Institute and Guangdong Provincial Key Laboratory of Laboratory Animals, Guangzhou 510080, Guangdong Province, China
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SWATH-MS Quantitative Proteomic Analysis of Deer Antler from Two Regenerating and Mineralizing Sections. BIOLOGY 2021; 10:biology10070679. [PMID: 34356534 PMCID: PMC8301299 DOI: 10.3390/biology10070679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2021] [Revised: 07/13/2021] [Accepted: 07/14/2021] [Indexed: 01/02/2023]
Abstract
Simple Summary Deer antler is a unique and astonishing case of annual regeneration in mammalians. Several studies have pointed out the potential for use of velvet antler extract as a nutraceutical supplement, among others, because of its anti-cancer activity. The study of antler regeneration and growth allow us to identify the main proteins and regulatory pathways involved in cell differentiation and regeneration. For this purpose, two sections of antlers (tips and middle sections) using ribs as controls were analyzed from a proteomic point of view. A total of 259 proteins mainly associated with antioxidant mechanisms and Wnt signalling pathways could be responsible for deer antler regeneration and these proteins may be linked to human health benefits. Further studies should be focused on discovering which proteins from velvet antler extracts are associated with these beneficial effects. Abstract Antlers are the only organ in the mammalian body that regenerates each year. They can reach growth rates of 1–3 cm/day in length and create more than 20 cm2/day of skin in the antler tips (their growth centers). Previous proteomic studies regarding antlers have focused on antler growth centers (tips) compared to the standard bone to detect the proteins involved in tissue growth. However, proteins of cell differentiation and regeneration will be more accurately detected considering more growing tissues. Thus, we set out to compare proteins expressed in antler tips (the highest metabolism rate and cell differentiation) vs. middle sections (moderate cell growth involving bone calcification), using ribs as controls. Samples were obtained in mid-June with antlers’ phenology corresponding to the middle of their growth period. Quantitative proteomic analysis identified 259 differentially abundant proteins mainly associated with antioxidant metabolic mechanisms, protein formation and Wnt signalling pathway, meanwhile, the mid antler section was linked to blood proteins. The high metabolic rate and subsequent risk of oxidative stress also seem to have resulted in strong antioxidant mechanisms. These results suggest that redox regulation of proteins is a key factor in the model of deer antler regeneration.
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Comparative antler proteome of sika deer from different developmental stages. Sci Rep 2021; 11:10484. [PMID: 34006919 PMCID: PMC8131589 DOI: 10.1038/s41598-021-89829-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/30/2021] [Indexed: 11/08/2022] Open
Abstract
Antler is a special bone tissue that has the ability to regenerate completely periodically. It is the fastest growing bone in the animal kingdom. Antler provides a valuable research model for bone growth and mineralization. Antler grows longitudinally by endochondral ossification with their growth center located in its tip. Many scholars have carried out detailed studies on morphology and gene expression of antler tip. However, few scholars have analyzed the protein expression patterns of antler tip at different development stages. This study used label-free proteomics approach to analyze the protein expression dynamics of the antler tip in six developmental periods (15, 25, 45, 65, 100 and 130 days after the previous antler cast) and costal cartilage. In result, 2052 proteins were confidently quantified, including 1937 antler proteins and 1044 costal cartilage proteins. Moreover, 913 antler core proteins and 132 antler-special proteins were obtained. Besides, the stages special proteins and differentially expressed proteins (DEPs) in different development stages were analyzed. A total of 875 DEPs were determined by one-way AVOVA. It is found that the growth period (15, 25, 45 and 65 days) showed more up-regulated protein including several chondrogenesis-associated proteins (collagen types II, collagen types XI, HAPLN1, PAPSS1 and PAPSS2). In ossification stages, the up-regulated proteins related with lysosome (CTSD, CTSB, MMP9, CAII) indicated that the antler has higher bone remodeling activity. Given the up-regulated expression of immune-related molecules (S100A7, CATHL7, LTF, AZU1, ELANE and MPO), we speculate that the local immune system may contribute to the ossification of antler tip. In conclusion, proteomics technology was used to deeply analyze the protein expression patterns of antler at different development stages. This provides a strong support for the research on the molecular regulation mechanism of rapid growth and ossification of velvet antler.
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Li C. Residual antler periosteum holds the potential to partially regenerate lost antler tissue. JOURNAL OF EXPERIMENTAL ZOOLOGY PART 2021; 335:386-395. [PMID: 33793094 DOI: 10.1002/jez.2451] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 02/08/2021] [Accepted: 02/10/2021] [Indexed: 01/19/2023]
Abstract
Deer antlers are the only mammalian organs that can fully regenerate, which relies on pedicle periosteum (PP). Interestingly during the growing phase, antlers themselves can regenerate partially lost antler tissue. However, what tissue type in the growing antlers fulfills this role is not known. Following antler removal during the growing phase, a "second" antler regenerates from the stump. In this study, the "second" antler growing from the cut antler base (AB) was examined in both red and sika deer. The results showed that all regenerating antlers were formed from the peripheral edge of the AB, where the antler periosteum (AnP) is located. The growth center showed a clear demarcation from the AB bone in red deer. Therefore, it is highly likely that AnP is the tissue that possesses the potential. Factors that might affect this potential were explored and the main factor was found to be AB calcification, which was controlled by rising androgens. Thus, the ultimate antler regeneration potential of the AnP was assessed through castration and repeated antler removal. The results demonstrated that the regeneration potential of AnP was somewhat limited and inferior to that of the PP. The ability of AnP to achieve partial regeneration may be evolutionarily conserved, as the regeneration of partially lost antlers within the season is secured; whereas, with PP, a new set of antlers in the next season is guaranteed. This two-level mechanism may signify how evolutionarily important it is for deer to possess reasonably intact antlers.
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Affiliation(s)
- Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun City, Jilin Province, China
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26
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Dong Z, Coates D. Bioactive Molecular Discovery Using Deer Antlers as a Model of Mammalian Regeneration. J Proteome Res 2021; 20:2167-2181. [PMID: 33769828 DOI: 10.1021/acs.jproteome.1c00003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The ability to activate and regulate stem cells during wound healing and tissue regeneration is a promising field that is resulting in innovative approaches in the field of regenerative medicine. The regenerative capacity of invertebrates has been well documented; however, in mammals, stem cells that drive organ regeneration are rare. Deer antlers are the only known mammalian structure that can annually regenerate to produce a tissue containing dermis, blood vessels, nerves, cartilage, and bone. The neural crest derived stem cells that drive this process result in antlers growing at up to 2 cm/day. Deer antlers thus provide superior attributes compared to lower-order animal models, when investigating the regulation of stem cell-based regeneration. Antler stem cells can therefore be used as a model to investigate the bioactive molecules, biological processes, and pathways involved in the maintenance of a stem cell niche, and their activation and differentiation during organ formation. This review examines stem cell-based regeneration with a focus on deer antlers, a neural crest stem cell-based mammalian regenerative structure. It then discusses the omics technical platforms highlighting the proteomics approaches used for investigating the molecular mechanisms underlying stem cell regulation in antler tissues.
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Affiliation(s)
- Zhen Dong
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin 9016, New Zealand
| | - Dawn Coates
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin 9016, New Zealand
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Anti-tumour activity of deer growing antlers and its potential applications in the treatment of malignant gliomas. Sci Rep 2021; 11:42. [PMID: 33420194 PMCID: PMC7794318 DOI: 10.1038/s41598-020-79779-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 12/10/2020] [Indexed: 02/05/2023] Open
Abstract
A recent study showed that antlers have evolved a high rate of growth due to the expression of proto-oncogenes and that they have also evolved to express several tumour suppressor genes to control the risk of cancer. This may explain why deer antler velvet (DAV) extract shows anti-tumour activity. The fast growth of antler innervation through the velvet in close association to blood vessels provides a unique environment to study the fast but non-cancerous proliferation of heterogeneous cell populations. We set out to study the anti-cancer effect of DAV in glioblastoma (GB) cell lines in comparison with temozolomide, a chemotherapeutic drug used to treat high-grade brain tumours. Here we report, for the first time, that DAV extract from the tip, but not from mid-parts of the antler, exhibits an anti-tumour effect in GB cell lines (T98G and A172) while being non-toxic in non-cancerous cell lines (HEK293 and HACAT). In T98G cells, DAV treatment showed reduced proliferation (37.5%) and colony-formation capacity (84%), inhibited migration (39%), induced changes in cell cycle progression, and promoted apoptosis. The anticancer activity of DAV extract as demonstrated by these results may provide a new therapeutic strategy for GB treatment.
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28
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Rössner GE, Costeur L, Scheyer TM. Antiquity and fundamental processes of the antler cycle in Cervidae (Mammalia). THE SCIENCE OF NATURE - NATURWISSENSCHAFTEN 2020; 108:3. [PMID: 33326046 PMCID: PMC7744388 DOI: 10.1007/s00114-020-01713-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 11/02/2020] [Accepted: 11/23/2020] [Indexed: 12/12/2022]
Abstract
The origins of the regenerative nature of antlers, being branched and deciduous apophyseal appendages of frontal bones of cervid artiodactyls, have long been associated with permanent evolutionary precursors. In this study, we provide novel insight into growth modes of evolutionary early antlers. We analysed a total of 34 early antlers affiliated to ten species, including the oldest known, dating from the early and middle Miocene (approx. 18 to 12 million years old) of Europe. Our findings provide empirical data from the fossil record to demonstrate that growth patterns and a regular cycle of necrosis, abscission and regeneration are consistent with data from modern antlers. The diverse histological analyses indicate that primary processes and mechanisms of the modern antler cycle were not gradually acquired during evolution, but were fundamental from the earliest record of antler evolution and, hence, explanations why deer shed antlers have to be rooted in basic histogenetic mechanisms. The previous interpretation that proximal circular protuberances, burrs, are the categorical traits for ephemerality is refuted.
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Affiliation(s)
- Gertrud E. Rössner
- Staatliche Naturwissenschaftliche Sammlungen Bayerns - Bayerische Staatssammlung für Paläontologie und Geologie, Richard Wagner Str. 10, 80333 München, Germany
- Department für Geo- und Umweltwissenschaften, Ludwig-Maximilians-Universität München, Richard-Wagner-Str. 10, 80333 München, Germany
| | - Loïc Costeur
- Naturhistorisches Museum Basel, Augustinergasse 2, 4001 Basel, Switzerland
| | - Torsten M. Scheyer
- Universität Zürich, Paläontologisches Institut und Museum, Karl Schmid-Strasse 4, 8006 Zürich, Switzerland
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Yao B, Wang C, Zhou Z, Zhang M, Zhao D, Bai X, Leng X. Comparative transcriptome analysis of the main beam and brow tine of sika deer antler provides insights into the molecular control of rapid antler growth. Cell Mol Biol Lett 2020; 25:42. [PMID: 32944020 PMCID: PMC7487962 DOI: 10.1186/s11658-020-00234-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 09/02/2020] [Indexed: 12/15/2022] Open
Abstract
Background Deer antlers have become a valuable model for biomedical research due to the capacities of regeneration and rapid growth. However, the molecular mechanism of rapid antler growth remains to be elucidated. The aim of the present study was to compare and explore the molecular control exerted by the main beam and brow tine during rapid antler growth. Methods The main beams and brow tines of sika deer antlers were collected from Chinese sika deer (Cervus nippon) at the rapid growth stage. Comparative transcriptome analysis was conducted using RNA-Seq technology. Differential expression was assessed using the DEGseq package. Functional Gene Ontology (GO) enrichment analysis was accomplished using a rigorous algorithm according to the GO Term Finder tool, and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway enrichment analysis was accomplished with the R function phyper, followed by the hypergeometric test and Bonferroni correction. Quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to verify the RNA levels for differentially expressed mRNAs. Results The expression levels of 16 differentially expressed genes (DEGs) involved in chondrogenesis and cartilage development were identified as significantly upregulated in the main beams, including transcription factor SOX-9 (Sox9), collagen alpha-1(II) chain (Col2a1), aggrecan core protein (Acan), etc. However, the expression levels of 17 DEGs involved in endochondral ossification and bone formation were identified as significantly upregulated in the brow tines, including collagen alpha-1(X) chain (Col10a1), osteopontin (Spp1) and bone sialoprotein 2 (Ibsp), etc. Conclusion These results suggest that the antler main beam has stronger growth capacity involved in chondrogenesis and cartilage development compared to the brow tine during rapid antler growth, which is mainly achieved through regulation of Sox9 and its target genes, whereas the antler brow tine has stronger capacities of endochondral bone formation and resorption compared to the main beam during rapid antler growth, which is mainly achieved through the genes involved in regulating osteoblast and osteoclast activities. Thus, the current research has deeply expanded our understanding of the intrinsic molecular regulation displayed by the main beam and brow tine during rapid antler growth.
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Affiliation(s)
- Baojin Yao
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130117 Jilin China
| | - Chaonan Wang
- College of traditional Chinese medicine, Changchun University of Chinese Medicine, Changchun, 130117 China
| | - Zhenwei Zhou
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130117 Jilin China
| | - Mei Zhang
- Innovation Practice Center, Changchun University of Chinese Medicine, Changchun, 130117 Jilin China
| | - Daqing Zhao
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130117 Jilin China
| | - Xueyuan Bai
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, 130117 Jilin China
| | - Xiangyang Leng
- The Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, 130117 Jilin China
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Su H, Yang C, Jin C, Zhang H, Yin C, Yang Y, Chen H, Jing L, Qi B, Zhao D, Bai X, Liu L. Comparative Metabolomics Study Revealed Difference in Central Carbon Metabolism between Sika Deer and Red Deer Antler. Int J Genomics 2020; 2020:7192896. [PMID: 32908856 PMCID: PMC7471787 DOI: 10.1155/2020/7192896] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 06/22/2020] [Indexed: 11/18/2022] Open
Abstract
The antler regeneration has been well studied for the past two decades and adopted in the regenerative medicine model for studying on developmental biology. Despite our growing knowledge of functional molecules regulating antler regeneration, we still do not know whether antler from different deer species possess the exact same mechanism or not. Our previous comparative study between sika deer and red deer suggests that the metabolic pathways between them are profoundly different based on protein level. Therefore, the metabolomic technology is used to identify and quantify the metabolites in antler samples, providing interesting insights into differential metabolite profile of antlers between sika deer and red deer. The distinct metabolic characteristics of sika deer compared to red deer provide an opportunity to explain why the red deer antler with a larger size. The enrichment analysis of differential metabolites showed that three pathways including glycine and serine metabolism, methionine metabolism, and pterine biosynthesis had a significant difference between two antler groups.
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Affiliation(s)
- Hang Su
- Practice Innovations Center, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Chonghui Yang
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Chenrong Jin
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - He Zhang
- Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Chengcheng Yin
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Yang Yang
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Haoyuan Chen
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Li Jing
- Practice Innovations Center, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Bin Qi
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Daqing Zhao
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Xueyuan Bai
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130117, China
| | - Li Liu
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun 130117, China
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Bi X, Zhai J, Xia Y, Li H. Analysis of genetic information from the antlers of Rangifer tarandus (reindeer) at the rapid growth stage. PLoS One 2020; 15:e0230168. [PMID: 32168333 PMCID: PMC7069613 DOI: 10.1371/journal.pone.0230168] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 02/21/2020] [Indexed: 01/22/2023] Open
Abstract
Reindeer is the only deer species in which both males and females regularly grow antlers, providing an excellent model for studying the rapid growth and annual regeneration of antlers. The study of genetic information from reindeer is the basis for revealing the unique mechanism of antler growth. In the present study, we obtained 18.86 GB of clean reads, which were assembled to obtain 94,575 unigenes (average length: 704.69). Among these reads, 30,980 sequences were identified by searching a database of known proteins and then annotated with Gene Ontology (GO) terms, Clusters of Orthologous Groups (COG) classifications and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. All 7,480 simple sequence repeats (SSRs) were detected. A total of 84,435 and 82,226 high-quality single-nucleotide polymorphisms (SNPs) were identified in male and female reindeer, respectively. We identified 31 genes that were highly expressed in reindeer antlers. These genes regulate cell activities that are closely associated with the process of rapid tissue growth. Our results provide a basis for studying reindeer antlers and for further studying the molecular genetics, population genetics, and functional genomics of reindeer.
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Affiliation(s)
- Xiaodan Bi
- College of Wildlife and Protected Area, Northeast Forestry University, Xiangfang District, China
- College of Chemistry and Life Science, Chifeng University, Hongshan District, China
| | - Jiancheng Zhai
- College of Wildlife and Protected Area, Northeast Forestry University, Xiangfang District, China
- School of Earth Sciences, East China University of Technology, China
| | - Yanling Xia
- College of Wildlife and Protected Area, Northeast Forestry University, Xiangfang District, China
- School of Earth Sciences, East China University of Technology, China
| | - Heping Li
- College of Wildlife and Protected Area, Northeast Forestry University, Xiangfang District, China
- * E-mail:
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Dong Z, Haines S, Coates D. Proteomic Profiling of Stem Cell Tissues during Regeneration of Deer Antler: A Model of Mammalian Organ Regeneration. J Proteome Res 2020; 19:1760-1775. [DOI: 10.1021/acs.jproteome.0c00026] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Zhen Dong
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
| | - Stephen Haines
- Proteins & Metabolites, AgResearch Lincoln Research Centre, Lincoln, New Zealand
| | - Dawn Coates
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, Dunedin, New Zealand
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Sun H, Sui Z, Wang D, Ba H, Zhao H, Zhang L, Li C. Identification of interactive molecules between antler stem cells and dermal papilla cells using an in vitro co-culture system. J Mol Histol 2020; 51:15-31. [PMID: 31858326 DOI: 10.1007/s10735-019-09853-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Accepted: 11/30/2019] [Indexed: 12/25/2022]
Abstract
Deer antlers are the only mammalian organs capable of complete renewal. Antler renewal is a stem cell-based [antler stem cells (ASCs)] process. Maintenance and activation of the ASCs require them to be located in a specialized microenvironment (niche), and to interact with the cells resident in the niche. Based on previous experiments we found that niche of the ASCs is provided by the closely associated enveloping skin, which currently was known includes dermal papilla cells (DPCs) and epidermal cells. Antler generation/regeneration are triggered by the interactions between ASCs and the niche. In the present study, we established an in vitro co-culture system in which ASCs and DPCs, were cultured together to mimic the in vivo state. A MLEFF strategy was adopted to identify the interactive molecules from the co-culture system. In total, 128 molecules were identified and over 60% belonged to exosomes. Important biological processes that were activated by these molecules included osteoblast differentiation, angiogenesis, and the PI3K-AKT signaling pathway. In so doing, we have significantly simplified the process for identifying interactive molecules, which may be the key signals for triggering antler formation/renewal. Further study of these molecules will help us to gain insights into the mechanism of mammalian organ regeneration.
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Affiliation(s)
- Hongmei Sun
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Zhigang Sui
- Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China
| | - Datao Wang
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Hengxing Ba
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Haiping Zhao
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China
| | - Lihua Zhang
- Key Laboratory of Separation Science for Analytical Chemistry, National Chromatographic R. & A. Center, Dalian Institute of Chemical Physics, Chinese Academy of Science, Dalian, China.
| | - Chunyi Li
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, Changchun, China.
- Changchun Sci-Tech University, Changchun, China.
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Rong X, Zhang G, Yang Y, Gao C, Chu W, Sun H, Wang Y, Li C. Transplanted Antler Stem Cells Stimulated Regenerative Healing of Radiation-induced Cutaneous Wounds in Rats. Cell Transplant 2020; 29:963689720951549. [PMID: 32907381 PMCID: PMC7784515 DOI: 10.1177/0963689720951549] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 07/18/2020] [Accepted: 07/29/2020] [Indexed: 12/29/2022] Open
Abstract
Radiation-induced cutaneous injury is the main side effect of radiotherapy. The injury is difficult to cure and the pathogenesis is complex. Mesenchymal stem cells (MSCs) serve as a promising candidate for cell-based therapy for the treatment of cutaneous wounds. The aim of the present study was to investigate whether antler stem cells (AnSCs) have better therapeutic effects on radiation-induced cutaneous injury than currently available ones. In this study, a rat model of cutaneous wound injury from Sr-90 radiation was used. AnSCs (1 × 106/500 μl) were injected through the tail vein on the first day of irradiation. Our results showed that compared to the control group, AnSC-treated rats exhibited a delayed onset (14 days versus 7 days), shorter recovery time (51 days versus 84 days), faster healing rate (100% versus 70% on day 71), and higher healing quality with more cutaneous appendages regenerated (21:10:7/per given area compared to those of rat and human MSCs, respectively). More importantly, AnSCs promoted much higher quality of healing compared to other types of stem cells, with negligible scar formation. AnSC lineage tracing results showed that the injected-dye-stained AnSCs were substantially engrafted in the wound healing tissue, indicating that the therapeutic effects of AnSCs on wound healing at least partially through direct participation in the wound healing. Expression profiling of the wound-healing-related genes in the healing tissue of AnSC group more resembled a fetal wound healing. Revealing the mechanism underlying this higher quality of wound healing by using AnSC treatment would help to devise more effective cell-based therapeutics for radiation-induced wound healing in clinics.
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Affiliation(s)
- Xiaoli Rong
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China
- The Third Hospital of Jilin University, Changchun, Jilin, China
| | - Guokun Zhang
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China
| | - Yanyan Yang
- The Third Hospital of Jilin University, Changchun, Jilin, China
| | - Chenmao Gao
- The Third Hospital of Jilin University, Changchun, Jilin, China
| | - Wenhui Chu
- School of Life Science, Taizhou University, Taizhou, China
| | - Hongmei Sun
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences (CAAS), Changchun, Jilin, China
| | - Yimin Wang
- The Third Hospital of Jilin University, Changchun, Jilin, China
| | - Chunyi Li
- Institute of Antler Science and Product Technology, Changchun Sci-Tech University, Changchun, Jilin, China
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Li C. Deer antlers: traditional Chinese medicine use and recent pharmaceuticals. ANIMAL PRODUCTION SCIENCE 2020. [DOI: 10.1071/an19168] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Deer velvet antlers (VA) have been used as a type of traditional Chinese medicine for over 2000 years, mainly for treating yang-deficiency syndromes. However, VA still largely remain a traditional remedy with scant science, although getting more attention as time goes. In recent years, our group has been trying to develop some efficacious drugs/functional food based on unique biological phenomena of VA, such as, for example, dead tissue (hard antler base) being attached to living tissue (pedicle) for over half a year without causing inflammation, a large-size wound (up to 10 cm in diameter) being left on top of a pedicle stump after previous antler casting healing within a week only with a negligible scar, and severely osteoporotic skeleton caused by intensive antler calcification fully reversing after the completion of antler calcification. Successful translation of these unique phenomena to clinical use would greatly benefit human health.
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Rong X, Chu W, Zhang H, Wang Y, Qi X, Zhang G, Wang Y, Li C. Antler stem cell-conditioned medium stimulates regenerative wound healing in rats. Stem Cell Res Ther 2019; 10:326. [PMID: 31744537 PMCID: PMC6862758 DOI: 10.1186/s13287-019-1457-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 09/23/2019] [Accepted: 10/16/2019] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND When the deer antler is cast, it leaves a cutaneous wound that can achieve scarless healing due to the presence of antler stem cells (ASCs). This provides an opportunity to study regenerative wound healing. METHODS In this study, we investigated the therapeutic effects and mechanism of antler stem cell-conditioned medium (ASC-CM) on cutaneous wound healing in rats. In vitro, we investigated the effects of the ASC-CM on proliferation of HUVEC and NIH-3T3 cell lines. In vivo, we evaluated the effects of ASC-CM on cutaneous wound healing using full-thickness skin punch-cut wounds in rats. RESULTS The results showed that ASC-CM significantly stimulated proliferation of the HUVEC and NIH-3T3 cells in vitro. In vivo, completion of healing of the rat wounds treated with ASC-CM was on day 16 (± 3 days), 9 days (± 2 days) earlier than the control group (DMEM); the area of the wounds treated with ASC-CM was significantly smaller (p < 0.05) than the two control groups. Further molecular characterization showed that the ratios of Col3A1/Col1A2, TGF-β3/TGF-β1, MMP1/TIMP1, and MMP3/TIMP1 significantly increased (p < 0.01) in the healed tissue in the ASC-CM group. CONCLUSIONS In conclusion, ASC-CM effectively accelerated the wound closure rate and enhanced the quality of healing, which might be through transforming wound dermal fibroblasts into the fetal counterparts. Therefore, the ASC-CM may have potential to be developed as a novel cell-free therapeutic for scarless wound healing.
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Affiliation(s)
- Xiaoli Rong
- Changchun Sci-Tech University, 1699 DongHua St., Shuangyang District, Changchun, Jilin 130022 China
- The Scientific Research Center, China-Japan Union Hospital of Jilin University, 126 Xiantai St., Changchun, Jilin 130033 China
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, 4899 Juye St., Changchun, Jilin 130112 China
| | - Wenhui Chu
- School of Life Science, Taizhou University, Taizhou, 318000 China
| | - Haiying Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Norman Bethune College of Medicine, Jilin University, 828 Xinmin St., Changchun, Jilin 130021 China
| | - Yusu Wang
- College of Chinese Medicinal Materials, Jilin Agricultural University, 2888 XinCheng St., Changchun, Jilin 130118 China
| | - Xiaoyan Qi
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, 4899 Juye St., Changchun, Jilin 130112 China
| | - Guokun Zhang
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, 4899 Juye St., Changchun, Jilin 130112 China
| | - Yimin Wang
- The Scientific Research Center, China-Japan Union Hospital of Jilin University, 126 Xiantai St., Changchun, Jilin 130033 China
| | - Chunyi Li
- Changchun Sci-Tech University, 1699 DongHua St., Shuangyang District, Changchun, Jilin 130022 China
- Institute of Special Animal and Plant Sciences, Chinese Academy of Agricultural Sciences, 4899 Juye St., Changchun, Jilin 130112 China
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Landete-Castillejos T, Kierdorf H, Gomez S, Luna S, García AJ, Cappelli J, Pérez-Serrano M, Pérez-Barbería J, Gallego L, Kierdorf U. Antlers - Evolution, development, structure, composition, and biomechanics of an outstanding type of bone. Bone 2019; 128:115046. [PMID: 31446115 DOI: 10.1016/j.bone.2019.115046] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 08/20/2019] [Accepted: 08/21/2019] [Indexed: 02/07/2023]
Abstract
Antlers are bony appendages of deer that undergo periodic regeneration from the top of permanent outgrowths (the pedicles) of the frontal bones. Of the "less familiar" bone types whose study was advocated by John Currey to gain a better understanding of structure-function relationships of mineralized tissues and organs, antlers were of special interest to him. The present review summarizes our current knowledge about the evolution, development, structure, mineralization, and biomechanics of antlers and how their formation is affected by environmental factors like nutrition. Furthermore, the potential role of antlers as a model in bone biology and several fields of biomedicine as well as their use as a monitoring tool in environmental studies are discussed.
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Affiliation(s)
- T Landete-Castillejos
- Instituto de Investigación en Recursos Cinegéticos, Universidad de Castilla-La Mancha, 02071 Albacete, Spain; Escuela Técnica Superior de Ingenieros Agrónomos y Montes, Universidad de Castilla-La Mancha, 02071 Albacete, Spain; Sección de Recursos Cinegéticos y Ganaderos, Instituto de Desarrollo Regional, Universidad de Castilla-La Mancha, 02071 Albacete, Spain.
| | - H Kierdorf
- Department of Biology, University of Hildesheim, 31141 Hildesheim, Germany
| | - S Gomez
- Universidad de Cádiz, 11071 Cádiz, Spain
| | - S Luna
- Universidad de Cádiz, 11071 Cádiz, Spain
| | - A J García
- Instituto de Investigación en Recursos Cinegéticos, Universidad de Castilla-La Mancha, 02071 Albacete, Spain; Escuela Técnica Superior de Ingenieros Agrónomos y Montes, Universidad de Castilla-La Mancha, 02071 Albacete, Spain; Sección de Recursos Cinegéticos y Ganaderos, Instituto de Desarrollo Regional, Universidad de Castilla-La Mancha, 02071 Albacete, Spain
| | - J Cappelli
- Instituto de Investigación en Recursos Cinegéticos, Universidad de Castilla-La Mancha, 02071 Albacete, Spain; Escuela Técnica Superior de Ingenieros Agrónomos y Montes, Universidad de Castilla-La Mancha, 02071 Albacete, Spain; Sección de Recursos Cinegéticos y Ganaderos, Instituto de Desarrollo Regional, Universidad de Castilla-La Mancha, 02071 Albacete, Spain
| | - M Pérez-Serrano
- Instituto de Investigación en Recursos Cinegéticos, Universidad de Castilla-La Mancha, 02071 Albacete, Spain; Escuela Técnica Superior de Ingenieros Agrónomos y Montes, Universidad de Castilla-La Mancha, 02071 Albacete, Spain; Sección de Recursos Cinegéticos y Ganaderos, Instituto de Desarrollo Regional, Universidad de Castilla-La Mancha, 02071 Albacete, Spain
| | - J Pérez-Barbería
- Instituto de Investigación en Recursos Cinegéticos, Universidad de Castilla-La Mancha, 02071 Albacete, Spain; Escuela Técnica Superior de Ingenieros Agrónomos y Montes, Universidad de Castilla-La Mancha, 02071 Albacete, Spain; Sección de Recursos Cinegéticos y Ganaderos, Instituto de Desarrollo Regional, Universidad de Castilla-La Mancha, 02071 Albacete, Spain
| | - L Gallego
- Instituto de Investigación en Recursos Cinegéticos, Universidad de Castilla-La Mancha, 02071 Albacete, Spain; Escuela Técnica Superior de Ingenieros Agrónomos y Montes, Universidad de Castilla-La Mancha, 02071 Albacete, Spain; Sección de Recursos Cinegéticos y Ganaderos, Instituto de Desarrollo Regional, Universidad de Castilla-La Mancha, 02071 Albacete, Spain
| | - U Kierdorf
- Department of Biology, University of Hildesheim, 31141 Hildesheim, Germany
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Su H, Tang X, Zhang X, Liu L, Jing L, Pan D, Sun W, He H, Yang C, Zhao D, Zhang H, Qi B. Comparative proteomics analysis reveals the difference during antler regeneration stage between red deer and sika deer. PeerJ 2019; 7:e7299. [PMID: 31346498 PMCID: PMC6642628 DOI: 10.7717/peerj.7299] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Accepted: 06/14/2019] [Indexed: 12/21/2022] Open
Abstract
Deer antler, as the only mammalian regenerative appendage, provides an optimal model to study regenerative medicine. Antler harvested from red deer or sika deer were mainly study objects used to disclose the mechanism underlying antler regeneration over past decades. A previous study used proteomic technology to reveal the signaling pathways of antler stem cell derived from red deer. Moreover, transcriptome of antler tip from sika deer provide us with the essential genes, which regulated antler development and regeneration. However, antler comparison between red deer and sika deer has not been well studied. In our current study, proteomics were employed to analyze the biological difference of antler regeneration between sika deer and red deer. The proteomics profile was completed by searching the UniProt database, and differentially expressed proteins were identified by bioinformatic software. Thirty-six proteins were highly expressed in red deer antler, while 144 proteins were abundant in sika deer. GO and KEGG analysis revealed that differentially expressed proteins participated in the regulation of several pathways including oxidative phosphorylation, ribosome, extracellular matrix interaction, and PI3K-Akt pathway.
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Affiliation(s)
- Hang Su
- Practice Innovations Center, Changchun University of Chinese Medicine, Changchun, China
| | - Xiaolei Tang
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Xiaocui Zhang
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Li Liu
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Li Jing
- Practice Innovations Center, Changchun University of Chinese Medicine, Changchun, China
| | - Daian Pan
- School of Clinical Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Weijie Sun
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - Huinan He
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - Chonghui Yang
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - Daqing Zhao
- Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun, China
| | - He Zhang
- School of Clinical Medicine, Changchun University of Chinese Medicine, Changchun, China
| | - Bin Qi
- College of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
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Ba H, Wang D, Wu W, Sun H, Li C. Single-cell transcriptome provides novel insights into antler stem cells, a cell type capable of mammalian organ regeneration. Funct Integr Genomics 2019; 19:555-564. [DOI: 10.1007/s10142-019-00659-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2018] [Accepted: 01/09/2019] [Indexed: 10/27/2022]
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Miller BM, Johnson K, Whited JL. Common themes in tetrapod appendage regeneration: a cellular perspective. EvoDevo 2019; 10:11. [PMID: 31236203 PMCID: PMC6572735 DOI: 10.1186/s13227-019-0124-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 06/08/2019] [Indexed: 01/13/2023] Open
Abstract
Complete and perfect regeneration of appendages is a process that has fascinated and perplexed biologists for centuries. Some tetrapods possess amazing regenerative abilities, but the regenerative abilities of others are exceedingly limited. The reasons underlying these differences have largely remained mysterious. A great deal has been learned about the morphological events that accompany successful appendage regeneration, and a handful of experimental manipulations can be reliably applied to block the process. However, only in the last decade has the goal of attaining a thorough molecular and cellular biological understanding of appendage regeneration in tetrapods become within reach. Advances in molecular and genetic tools for interrogating these remarkable events are now allowing for unprecedented access to the fundamental biology at work in appendage regeneration in a variety of species. This information will be critical for integrating the large body of detailed observations from previous centuries with a modern understanding of how cells sense and respond to severe injury and loss of body parts. Understanding commonalities between regenerative modes across diverse species is likely to illuminate the most important aspects of complex tissue regeneration.
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Affiliation(s)
- Bess M. Miller
- Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave, Cambridge, MA 02138 USA
| | - Kimberly Johnson
- Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave, Cambridge, MA 02138 USA
| | - Jessica L. Whited
- Department of Stem Cell and Regenerative Biology, Harvard University, 7 Divinity Ave, Cambridge, MA 02138 USA
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Wang D, Berg D, Ba H, Sun H, Wang Z, Li C. Deer antler stem cells are a novel type of cells that sustain full regeneration of a mammalian organ-deer antler. Cell Death Dis 2019; 10:443. [PMID: 31165741 PMCID: PMC6549167 DOI: 10.1038/s41419-019-1686-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 04/19/2019] [Accepted: 05/19/2019] [Indexed: 12/14/2022]
Abstract
Deer antlers are extraordinary mammalian organs that can fully regenerate annually. Antler renewal is a stem cell-based epimorphic process and antler stem (AS) cells can initiate de novo generation of antlers in postnatal mammals. However, although being called stem cells, the AS cells have not been characterized at molecular level based on the stem cell criteria. Comprehensive characterization of the AS cells would undoubtedly help to decipher the mechanism underlying the full regeneration of deer antlers, the only case of stem cell-based epimorphic regeneration in mammals. In the present study, three types of AS cells (antlerogenic periosteal cells APCs, for initial pedicle and first antler formation; pedicle periosteal cells PPC, for annual antler regeneration; and reserve mesenchyme cells RMCs, for rapid antler growth), were isolated for comprehensive molecular characterization. A horn-growth-related gene, RXFP2, was found to be expressed only in AS cells lineages but not in the facial periosteal cells (FPCs, locates geographically in the vicinity of the APCs or PPCs), suggesting the RXFP2 might be a specific marker for the AS cell lineage in deer. Our results demonstrated that AS cells expressed classic MSC markers including surface markers CD73, CD90, CD105 and Stro-1. They also expressed some of the markers including Tert, Nestin, S100A4, nucleostemin and C-Myc, suggesting that they have some attributes of the ESCs. Microinjection of male APC into deer blastocysts resulted in one female foetus (110 days gestation) recovered with obvious pedicle primordia with both male and female genotype detected in the ovary. In conclusion, the AS cells should be defined as MSCs but with partial attributes of ESCs.
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Affiliation(s)
- Datao Wang
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, 4899 Juye Street, Changchun, 130112, China
| | - Debbie Berg
- AgResearch Ltd, Ruakura Agricultural Centre, 10 Bisley Road, Hamilton, 3214, New Zealand
| | - Hengxing Ba
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, 4899 Juye Street, Changchun, 130112, China
| | - Hongmei Sun
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, 4899 Juye Street, Changchun, 130112, China
| | - Zhen Wang
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, 4899 Juye Street, Changchun, 130112, China
| | - Chunyi Li
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, 4899 Juye Street, Changchun, 130112, China.
- Changchun Sci-Tech University, Changchun, 130600, China.
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42
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Ba H, Wang D, Yau TO, Shang Y, Li C. Transcriptomic analysis of different tissue layers in antler growth Center in Sika Deer (Cervus nippon). BMC Genomics 2019; 20:173. [PMID: 30836939 PMCID: PMC6402185 DOI: 10.1186/s12864-019-5560-1] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 02/22/2019] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND With the unprecedented rapid growth rate (up to 2.75 cm/day), velvet antler is an invaluable model for the identification of potent growth factors and signaling networks for extremely fast growing tissues, mainly cartilage. Antler growth center (AGC) locates in its tip and consists of five tissue layers: reserve mesenchyme (RM), precartilage (PC), transition zone (TZ), cartilage (CA) and mineralized cartilage (MC). The aim of this study was to investigate the transcription dynamics in the AGC using RNA-seq technology. RESULTS Five tissue layers in the AGC were collected from three 3-year-old male sika deer using our previously reported sampling method (morphologically distinguishable). After sequencing (15 samples; triplicates/tissue layer), we assembled a reference transcriptome de novo and used RNA-seq to measure gene expression profiles across these five layers. Nine differentially expressed genes (DEGs) were selected from our data and subsequently verified using qRT-PCR. The results showed a high consistency with the RNA-seq results (R2 = 0.80). Nine modules were constructed based on co-expression network analysis, and these modules contained 370 hub genes. These genes were found to be mainly involved in mesenchymal progenitor cell proliferation, chondrogenesis, osteogenesis and angiogenesis. Combination of our own results with the previously published reports, we found that Wnt signaling likely plays a key role not only in stimulating the antler stem cells or their immediate progeny, but also in promoting chondrogenesis and osteogenesis during antler development. CONCLUSION We have successfully assembled a reference transcriptome, generated gene expression profiling across the five tissue layers in the AGC, and identified nine co-expressed modules that contain 370 hub genes and genes predorminantly expressed in and highly relevant to each tissue layer. We believe our findings have laid the foundation for the identification of novel genes for rapid proliferation and chondrogenic differentiation of antler cells.
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Affiliation(s)
- Hengxing Ba
- State Key Laboratory for Molecular Biology of Special Wild Economic Animals, Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, 130112 China
| | - Datao Wang
- State Key Laboratory for Molecular Biology of Special Wild Economic Animals, Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, 130112 China
| | - Tung On Yau
- College of Science and Technology, Nottingham Trent University, Clifton Campus, Nottingham, NG11 8NS UK
| | - Yudong Shang
- State Key Laboratory for Molecular Biology of Special Wild Economic Animals, Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, 130112 China
| | - Chunyi Li
- State Key Laboratory for Molecular Biology of Special Wild Economic Animals, Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, 130112 China
- Changchun Sci-Tech University, Changchun, 130600 China
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Alibardi L. Organ regeneration evolved in fish and amphibians in relation to metamorphosis: Speculations on a post-embryonic developmental process lost in amniotes after the water to land transition. Ann Anat 2019; 222:114-119. [DOI: 10.1016/j.aanat.2018.12.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2018] [Revised: 12/10/2018] [Accepted: 12/11/2018] [Indexed: 02/06/2023]
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Wang D, Ba H, Li C, Zhao Q, Li C. Proteomic Analysis of Plasma Membrane Proteins of Antler Stem Cells Using Label-Free LC⁻MS/MS. Int J Mol Sci 2018; 19:3477. [PMID: 30400663 PMCID: PMC6275008 DOI: 10.3390/ijms19113477] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 10/31/2018] [Accepted: 11/03/2018] [Indexed: 12/16/2022] Open
Abstract
Deer antlers are unusual mammalian organs that can fully regenerate after annual shedding. Stem cells resident in the pedicle periosteum (PPCs) provide the main cell source for antler regeneration. Central to various cellular processes are plasma membrane proteins, but the expression of these proteins has not been well documented in antler regeneration. In the present study, plasma membrane proteins of PPCs and facial periosteal cells (FPCs) were analyzed using label-free liquid chromatography⁻mass spetrometry (LC⁻MS/MS). A total of 1739 proteins were identified. Of these proteins, 53 were found solely in the PPCs, 100 solely in the FPCs, and 1576 co-existed in both PPCs and FPCs; and 39 were significantly up-regulated in PPCs and 49 up-regulated in FPCs. In total, 226 gene ontology (GO) terms were significantly enriched from the differentially expressed proteins (DEPs). Five clusters of biological processes from these GO terms comprised responses to external stimuli, signal transduction, membrane transport, regulation of tissue regeneration, and protein modification processes. Further studies are required to demonstrate the relevancy of these DEPs in antler stem cell biology and antler regeneration.
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Affiliation(s)
- Datao Wang
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun 130112, China.
| | - Hengxing Ba
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun 130112, China.
| | - Chenguang Li
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun 130112, China.
- College of Life Sciences, Jilin Agricultural University, Changchun 130118, China.
| | - Quanmin Zhao
- College of Life Sciences, Jilin Agricultural University, Changchun 130118, China.
| | - Chunyi Li
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun 130112, China.
- Department of Biology, Changchun Sci-Tech University, Changchun 130600, China.
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He Y, Hasan I, Keilig L, Fischer D, Ziegler L, Abboud M, Wahl G, Bourauel C. Biomechanical characteristics of immediately loaded and osseointegration dental implants inserted into Sika deer antler. Med Eng Phys 2018; 59:8-14. [PMID: 30017665 DOI: 10.1016/j.medengphy.2018.04.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Revised: 03/13/2018] [Accepted: 04/16/2018] [Indexed: 10/28/2022]
Abstract
This study aimed to compare biomechanical characteristics of immediately loaded (IL) and osseointegrated (OS) dental implants inserted into Sika deer antler and lay a foundation for developing an alternative animal model for dental implants studies. Two implants per antler were inserted. One implant was loaded immediately via a self-developed loading device; the other was submerged and unloaded as control. IL implants were harvested after different loading periods. The unloaded implants were collected after OS and the shedding of antler. Specimens were scanned by µCT scanner and finite element models were generated. A vertical force of 10 N was applied on the implant. The mean values of maximum displacements, stresses and strains were compared. The results showed that the density of antler tissue around the implants dramatically increased as the loading time increased. After shedding the antler, 3 pairs of antlers were collected and the density of antler tissue remained in a similar value in all specimens. The maximum values of displacement and stresses in implant and stresses and strains in antler tissue were significantly different among OS models. In one antler, all the biomechanical parameters of IL model were significantly higher than those of OS model of the same animal (P < 0.05) and wider distributions were obtained from IL model. It can be concluded that implants inserted into Sika deer antler might not disturb the growth and calcification process of antler and the use of Sika deer antler model is a promising alternative for implant studies that does not require animal sacrifice.
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Affiliation(s)
- Yun He
- Orofacial Reconstruction and Regeneration Laboratory, Department of Oral and Maxillofacial Surgery, the Hospital of Stomatology, Southwest Medical University, Luzhou, China; Oral Technology, Dental School, University of Bonn, Welschnonnenstr. 17, 53111 Bonn, Germany
| | - Istabrak Hasan
- Oral Technology, Dental School, University of Bonn, Welschnonnenstr. 17, 53111 Bonn, Germany; Department of Prosthetic Dentistry, Preclinical Education and Materials Science, Dental School, University of Bonn, Bonn, Germany.
| | - Ludger Keilig
- Oral Technology, Dental School, University of Bonn, Welschnonnenstr. 17, 53111 Bonn, Germany; Department of Prosthetic Dentistry, Preclinical Education and Materials Science, Dental School, University of Bonn, Bonn, Germany
| | - Dominik Fischer
- Raptor Center and Wildlife Parc Hellenthal, Hellenthal, Germany; Clinic for Birds, Reptiles, Amphibians and Fish, Veterinary Faculty, Justus Liebig University Giessen, Giessen, Germany
| | - Luisa Ziegler
- Clinic for Birds, Reptiles, Amphibians and Fish, Veterinary Faculty, Justus Liebig University Giessen, Giessen, Germany
| | - Markus Abboud
- Department of Prosthodontics and Digital Technology, School of Dental Medicine, Stony Brook University, 1104 Westchester Hall, Stony Brook, New York
| | - Gerhard Wahl
- Department of Oral Surgery, Dental School, University of Bonn, Bonn, Germany
| | - Christoph Bourauel
- Oral Technology, Dental School, University of Bonn, Welschnonnenstr. 17, 53111 Bonn, Germany
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Wang DT, Chu WH, Sun HM, Ba HX, Li CY. Expression and Functional Analysis of Tumor-Related Factor S100A4 in Antler Stem Cells. J Histochem Cytochem 2017; 65:579-591. [PMID: 28832242 PMCID: PMC5624364 DOI: 10.1369/0022155417727263] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 07/27/2017] [Indexed: 01/09/2023] Open
Abstract
Annual antler renewal is a stem cell-based epimorphic process driven by antler stem cells (ASCs) resident in antlerogenic periosteum (AP). Antlerogenic periosteal cells express a high level of S100A4, a metastasis-associated protein, which intrigued us to explore what role S100A4 could play in antler regeneration. The present study set out to investigate expression and effects of S100A4 in the ASCs and their progeny. The results showed that not only did cells from the AP express a high level of S100A4, but also the pedicle periosteum and the antler growth center. In the antler growth center, we found S100A4-positive cells were specifically located in blood vessel walls and in vascularized areas. In vitro, recombinant deer S100A4 protein stimulated the proliferation of the AP cells, promoted proliferation, migration and tube formation of human vascular endothelial cells, and enhanced migration of Hela cells, but not AP cells. These findings demonstrated that S100A4 in the ASCs may play a significant role in stimulating angiogenesis, proliferation, but not motility, of ASCs. Deer antlers offer a unique model to explore how rapid cell proliferation with a high level of S100A4 expression is elegantly regulated without becoming cancerous.
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Affiliation(s)
- Da-tao Wang
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
- State Kay Laboratory for Molecular Biology of Special Economic Animals, Changchun, People’s Republic of China
| | - Wen-hui Chu
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
- State Kay Laboratory for Molecular Biology of Special Economic Animals, Changchun, People’s Republic of China
| | - Hong-mei Sun
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
| | - Heng-xing Ba
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
- State Kay Laboratory for Molecular Biology of Special Economic Animals, Changchun, People’s Republic of China
| | - Chun-yi Li
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, People’s Republic of China
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Colitti M. Distribution of BDNF and TrkB isoforms in growing antler tissues of red deer. Ann Anat 2017; 213:33-46. [PMID: 28602824 DOI: 10.1016/j.aanat.2017.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2017] [Revised: 05/16/2017] [Accepted: 05/16/2017] [Indexed: 11/26/2022]
Abstract
Antlers are the cranial appendages of deer that regenerate each year. This renewal provides a model to explore molecules involved in mammalian organ regeneration. The cellular distributions of the brain-derived neurotrophic factor (BDNF) and the isoforms of its cognate receptor Trk tyrosine kinase receptor (TrkB) were localized by immunohistochemistry in sections of growing red deer antler. BDNF and TrkB full length were widely expressed in the integument, perichondrium, periosteum and bone. The truncated isoform receptor was particularly evidenced in integument and vascular inner dermis, but very light reaction was observed in cartilage and bone, both at the site of endochondral and intramembranous ossification. These observations were also assessed at transcriptional level by RT-PCR analyses. The highest expression of all genes significantly occurred in chondroprogenitor cells; however the full-length TrkB receptor was down regulated in osteocartilaginous compartments, in which the truncated isoform was up regulated. The truncated isoform is a dominant-negative receptor that inhibits the full length receptor signalling, even if the truncated isoform not only has this function. This study establishes the presence of BDNF and its receptor in the different cellular compartments of growing antler. Their transcripts assessed by RT-PCR indicate a local synthesis of these molecules that may contribute to the modulation of antler growth, acting as autocrine and/or paracrine factors independently of nerve supply. Among the plethora of other molecular signals and growth factors affecting the antler growth, the local production of BDNF and its cognate receptor could be of interest in understanding their role in antler renewal and to delineate the different involvement of the receptor isoforms.
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Affiliation(s)
- M Colitti
- Department of Agricultural, Food, Environmental and Animal Sciences, University of Udine, via delle Scienze, 206, 33100 Udine, Italy.
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Regeneration and Regrowth Potentials of Digit Tips in Amphibians and Mammals. Int J Cell Biol 2017; 2017:5312951. [PMID: 28487741 PMCID: PMC5402240 DOI: 10.1155/2017/5312951] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 03/09/2017] [Indexed: 12/27/2022] Open
Abstract
Tissue regeneration and repair have received much attention in the medical field over the years. The study of amphibians, such as newts and salamanders, has uncovered many of the processes that occur in these animals during full-limb/digit regeneration, a process that is highly limited in mammals. Understanding these processes in amphibians could shed light on how to develop and improve this process in mammals. Amputation injuries in mammals usually result in the formation of scar tissue with limited regrowth of the limb/digit; however, it has been observed that the very tips of digits (fingers and toes) can partially regrow in humans and mice under certain conditions. This review will summarize and compare the processes involved in salamander limb regeneration, mammalian wound healing, and digit regeneration in mice and humans.
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Dong Z, Ba H, Zhang W, Coates D, Li C. iTRAQ-Based Quantitative Proteomic Analysis of the Potentiated and Dormant Antler Stem Cells. Int J Mol Sci 2016; 17:1778. [PMID: 27792145 PMCID: PMC5133779 DOI: 10.3390/ijms17111778] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 10/08/2016] [Accepted: 10/16/2016] [Indexed: 01/13/2023] Open
Abstract
As the only known organ that can completely regenerate in mammals, deer antler is of real significance in the field of regenerative medicine. Recent studies have shown that the regenerative capacity of the antlers comes from the pedicle periosteum and the cells resident in the periosteum possess the attributes of stem cells. Currently, the molecular mechanism of antler regeneration remains unclear. In the present study, we compared the potentiated and dormant antler stem cells using isobaric tags for the relative and absolute quantification (iTRAQ) labeling of the peptides, coupled with two-dimensional liquid chromatography-tandem mass spectrometry (LC-MS/MS) to compare the proteome profiles. Proteins were identified by searching against the NCBI nr database and our own Cervine transcriptome database, and bioinformatics analysis was conducted to identify the differentially expressed proteins. Based on this searching strategy, we identified 169 differentially expressed proteins in total, consisting of 70 up- and 99 down-regulated in the potentiated vs. dormant antler stem cells. Reliability of the iTRAQ was confirmed via quantitative real-time polymerase chain reaction (qRT-PCR) to measure the expression of selected genes. We identified transduction pathways through the Kyoto Encyclopedia of Genes and Genomes (KEGG) database, such as HIF-1 and PI3K-AKT signaling pathways that play important roles in regulating the regeneration of antlers. In summary, the initiation stage of antler regeneration, a process from dormant to potentiated states in antler stem cells, is regulated by multiple proteins and complicated signal networks.
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Affiliation(s)
- Zhen Dong
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun 130112, China.
- State Key Laboratory for Molecular Biology of Special Economic Animals, Changchun 130112, China.
| | - Hengxing Ba
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun 130112, China.
- State Key Laboratory for Molecular Biology of Special Economic Animals, Changchun 130112, China.
| | - Wei Zhang
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun 130112, China.
- State Key Laboratory for Molecular Biology of Special Economic Animals, Changchun 130112, China.
| | - Dawn Coates
- Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, PO Box 647, Dunedin 9054, New Zealand.
| | - Chunyi Li
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun 130112, China.
- State Key Laboratory for Molecular Biology of Special Economic Animals, Changchun 130112, China.
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50
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Yang C, Lu X, Sun H, Chu WH, Li C. Analysis of Genomewide DNA Methylation Reveals Differences in DNA Methylation Levels between Dormant and Naturally as well as Artificially Potentiated Pedicle Periosteum of Sika Deer (Cervus nippon). JOURNAL OF EXPERIMENTAL ZOOLOGY. PART B, MOLECULAR AND DEVELOPMENTAL EVOLUTION 2016; 326:375-383. [PMID: 27554771 DOI: 10.1002/jez.b.22695] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 07/19/2016] [Accepted: 07/23/2016] [Indexed: 11/10/2022]
Abstract
Deer antlers are the only mammalian appendages that can fully regenerate each year from the permanent bony protuberances of the frontal bones, called pedicles. Pedicle periosteum (PP) is the key tissue for antler regeneration and the source of antler stem cells. The distal one third of the PP has acquired the ability to regenerate antlers and is termed the potentiated PP (PPP), whereas the proximal two thirds of the PP requires further interactions within its niche to launch antler regeneration and is termed the dormant PP (DPP). However, the molecular mechanisms underlying the process of potentiation from the DPP to the PPP are unknown. In this study, we used the fluorescence-labeled methylation-sensitive amplified polymorphism method to assess the levels of DNA methylation in both cells and tissues of the PPP and the DPP. The results showed that the levels of DNA methylation were significantly lower in the PPP compared to the DPP (P < 0.05). Therefore, DNA demethylation may be involved in the process of this potentiation. This involvement was further confirmed by functional testing by artificially creating a potentiated PP (aPPP) from DPP tissue. Moreover, we identified 15 methylated fragments by the methylation sensitive amplified polymorphism method that are either unique to the PPP or the DPP, which were further confirmed by Southern blot analysis. Taken together, our data suggest that DNA demethylation is involved in the process of PP potentiation, which is a prerequisite step for the initiation of antler regeneration. These findings provide the first experimental evidence to link epigenetic regulation and mammalian appendage regeneration.
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Affiliation(s)
- Chun Yang
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, People's Republic of China
- State key Laboratory for Molecular Biology of Special Economic Animals, Changchun, People's Republic of China
| | - Xiao Lu
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, People's Republic of China
- State key Laboratory for Molecular Biology of Special Economic Animals, Changchun, People's Republic of China
| | - Hongmei Sun
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, People's Republic of China
- State key Laboratory for Molecular Biology of Special Economic Animals, Changchun, People's Republic of China
| | - Wen Hui Chu
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, People's Republic of China
- State key Laboratory for Molecular Biology of Special Economic Animals, Changchun, People's Republic of China
| | - Chunyi Li
- Institute of Special Wild Economic Animals and Plants, Chinese Academy of Agricultural Sciences, Changchun, People's Republic of China.
- State key Laboratory for Molecular Biology of Special Economic Animals, Changchun, People's Republic of China.
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