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Kim J, Song SY, Sung JH. Recent Advances in Drug Development for Hair Loss. Int J Mol Sci 2025; 26:3461. [PMID: 40331976 PMCID: PMC12026576 DOI: 10.3390/ijms26083461] [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: 03/07/2025] [Revised: 03/29/2025] [Accepted: 04/03/2025] [Indexed: 05/08/2025] Open
Abstract
Hair loss disorders pose a substantial global health burden, affecting millions of individuals and significantly impacting quality of life. Despite the widespread use of approved therapeutics like minoxidil and finasteride, their clinical efficacy remains limited. These challenges underscore the pressing need for more targeted and effective therapeutic solutions. This review examines the latest innovations in hair loss drug discovery, with a focus on small-molecule inhibitors, biologics, and stem cell-based therapies. By integrating insights from molecular mechanisms and leveraging advancements in research methods, the development of next-generation therapeutics holds the potential to transform the clinical management of hair loss disorders. Future drug development for hair loss disorders should prioritize antibody therapy and cell-based treatments, as these approaches offer unprecedented opportunities to address the limitations of existing options. Antibody therapies enable precise targeting of key molecular pathways involved in hair follicle regulation, providing highly specific and effective interventions. Similarly, cell-based therapies, including stem cell transplantation and dermal papilla cell regeneration, directly address the regenerative capacity of hair follicles, offering transformative potential for hair restoration.
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Affiliation(s)
- Jino Kim
- New Hair Institute, Seoul 06034, Republic of Korea;
| | - Seung-Yong Song
- Institute for Human Tissue Restoration, Department of Plastic and Reconstructive Surgery, Yonsei University College of Medicine, Seoul 06134, Republic of Korea;
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Xu S, Akhatayeva Z, Liu J, Feng X, Yu Y, Badaoui B, Esmailizadeh A, Kantanen J, Amills M, Lenstra JA, Johansson AM, Coltman DW, Liu GE, Curik I, Orozco-terWengel P, Paiva SR, Zinovieva NA, Zhang L, Yang J, Liu Z, Wang Y, Yu Y, Li M. Genetic advancements and future directions in ruminant livestock breeding: from reference genomes to multiomics innovations. SCIENCE CHINA. LIFE SCIENCES 2025; 68:934-960. [PMID: 39609363 DOI: 10.1007/s11427-024-2744-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 09/24/2024] [Indexed: 11/30/2024]
Abstract
Ruminant livestock provide a rich source of products, such as meat, milk, and wool, and play a critical role in global food security and nutrition. Over the past few decades, genomic studies of ruminant livestock have provided valuable insights into their domestication and the genetic basis of economically important traits, facilitating the breeding of elite varieties. In this review, we summarize the main advancements for domestic ruminants in reference genome assemblies, population genomics, and the identification of functional genes or variants for phenotypic traits. These traits include meat and carcass quality, reproduction, milk production, feed efficiency, wool and cashmere yield, horn development, tail type, coat color, environmental adaptation, and disease resistance. Functional genomic research is entering a new era with the advancements of graphical pangenomics and telomere-to-telomere (T2T) gap-free genome assembly. These advancements promise to improve our understanding of domestication and the molecular mechanisms underlying economically important traits in ruminant livestock. Finally, we provide new perspectives and future directions for genomic research on ruminant genomes. We suggest how ever-increasing multiomics datasets will facilitate future studies and molecular breeding in livestock, including the potential to uncover novel genetic mechanisms underlying phenotypic traits, to enable more accurate genomic prediction models, and to accelerate genetic improvement programs.
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Affiliation(s)
- Songsong Xu
- Frontiers Science Center for Molecular Design Breeding (MOE); State Key Laboratory of Animal Biotech Breeding; College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Zhanerke Akhatayeva
- Institute of Grassland Research, Chinese Academy of Agricultural Sciences, Hohhot, 010010, China
| | - Jiaxin Liu
- Frontiers Science Center for Molecular Design Breeding (MOE); State Key Laboratory of Animal Biotech Breeding; College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Xueyan Feng
- Frontiers Science Center for Molecular Design Breeding (MOE); State Key Laboratory of Animal Biotech Breeding; College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Yi Yu
- Frontiers Science Center for Molecular Design Breeding (MOE); State Key Laboratory of Animal Biotech Breeding; College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Bouabid Badaoui
- Laboratory of Biodiversity, Ecology and Genome, Department of Biology, Faculty of Sciences Rabat, Mohammed V University, Rabat, 10106, Morocco
| | - Ali Esmailizadeh
- Department of Animal Science, Faculty of Agriculture, Shahid Bahonar University of Kerman, Kerman, 76169-133, Iran
| | - Juha Kantanen
- Production Systems, Natural Resources Institute Finland (Luke), Jokioinen, FI-31600, Finland
| | - Marcel Amills
- Department of Animal Genetics, Center for Research in Agricultural Genomics (CRAG), CSIC-IRTA-UAB-UB, Campus de la Universitat Autónoma de Barcelona, Bellaterra, 08193, Spain
- Departament de Ciència Animal i dels Aliments, Universitat Autónoma de Barcelona, Bellaterra, 08193, Spain
| | - Johannes A Lenstra
- Faculty of Veterinary Medicine, Utrecht University, Utrecht, 3584, The Netherlands
| | - Anna M Johansson
- Department of Animal Breeding and Genetics, Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Uppsala, 75007, Sweden
| | - David W Coltman
- Department of Biological Sciences, University of Alberta, Edmonton, Alberta, T6G 2E9, Canada
- Department of Biology, Western University, London, Ontario, N6A 5B7, Canada
| | - George E Liu
- Animal Genomics and Improvement Laboratory, BARC, USDA-ARS, Beltsville, MD, 20705, USA
| | - Ino Curik
- Department of Animal Science, Faculty of Agriculture, University of Zagreb, Zagreb, 10000, Croatia
- Institute of Animal Sciences, Hungarian University of Agriculture and Life Sciences (MATE), Kaposvár, 7400, Hungary
| | | | - Samuel R Paiva
- Embrapa Genetic Resources and Biotechnology, Laboratory of Animal Genetics, Brasília, Federal District, 70770917, Brazil
| | - Natalia A Zinovieva
- L.K. Ernst Federal Science Center for Animal Husbandry, Moscow Region, Podolsk, 142132, Russian Federation
| | - Linwei Zhang
- Department of Neurology, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Ji Yang
- Frontiers Science Center for Molecular Design Breeding (MOE); State Key Laboratory of Animal Biotech Breeding; College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Zhihong Liu
- College of Animal Science, Inner Mongolia Agricultural University, Hohhot, 010018, China
| | - Yachun Wang
- Frontiers Science Center for Molecular Design Breeding (MOE); State Key Laboratory of Animal Biotech Breeding; College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Ying Yu
- Frontiers Science Center for Molecular Design Breeding (MOE); State Key Laboratory of Animal Biotech Breeding; College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China
| | - Menghua Li
- Frontiers Science Center for Molecular Design Breeding (MOE); State Key Laboratory of Animal Biotech Breeding; College of Animal Science and Technology, China Agricultural University, Beijing, 100193, China.
- Sanya Institute of China Agricultural University, Sanya, 572024, China.
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Xu Z, Ponek A, Thomas J, Qyang Y. Generation of Orthogonal Gradients of the Matrix Stiffness and Chemotactic Cues in a Suspended Array of Hydrogel to Study hMSCs Migration. ACS Sens 2025; 10:1722-1728. [PMID: 40021359 DOI: 10.1021/acssensors.4c02793] [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] [Indexed: 03/03/2025]
Abstract
Stem cell migration is a tightly regulated process in vivo, orchestrated by a collection of mechanical and chemotactic cues via concentration gradients. A variety of in vitro assays have been developed to facilitate cell migration studies; however, very few assays allow the investigation of both matrix stiffness and chemotactic cues on cell migration within a single device, especially in a three-dimensional (3D) environment. Here, we develop a microfluidic device that can produce 3D orthogonal gradients of matrix stiffness and chemotactic cues with varied steepness in a suspended array of hydrogel cylinders. The device's working principle is the formation of diffusion-driven concentration gradients within a suspended array of hydrogel cylinders between a source and a sink. Device fabrication is based on poly(dimethylsiloxane) (PDMS) replica molding, followed by assembly on a glass substrate. To validate this device, we study the migration of human mesenchymal stem cells (hMSCs) in response to orthogonal gradients of matrix stiffness and stromal cell-derived factor 1 alpha (SDF-1α). This technology has the potential to be applied to various cell types, facilitating exploration in different cellular contexts.
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Affiliation(s)
- Zhen Xu
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06511,United States
- Yale Stem Cell Center, New Haven, Connecticut 06520, United States
| | - Anna Ponek
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06511,United States
| | - Jordan Thomas
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06511,United States
| | - Yibing Qyang
- Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06511,United States
- Yale Stem Cell Center, New Haven, Connecticut 06520, United States
- Department of Pathology, Yale School of Medicine, New Haven, Connecticut 06520, United States
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut 06520, United States
- Department of Biomedical Engineering, Yale University, New Haven, Connecticut 06519, United States
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Li Y, Song G, Jiang Y, Zhao H, Zhu Y, Song S, Wang L, Wu X. Single-cell transcriptome analysis of stem cells from human exfoliated deciduous teeth investigating functional heterogeneity in immunomodulation. Sci Rep 2024; 14:31279. [PMID: 39732760 PMCID: PMC11682124 DOI: 10.1038/s41598-024-82734-8] [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: 08/29/2024] [Accepted: 12/09/2024] [Indexed: 12/30/2024] Open
Abstract
Mesenchymal stem cells (MSCs) have been widely used in the treatment of various inflammatory diseases. The inadequate understanding of MSCs and their heterogeneity can impact the immune environment, which may be the cause of the good outcomes of MSCs-based therapy that cannot always be achieved. Recently, stem cells from human exfoliated deciduous teeth (SHED) showed great potential in inflammatory and autoimmune diseases due to their immature properties compared with MSCs. In our study, single-cell RNA sequencing (scRNA-seq) revealed that SHED in a low differentiation state (S7) exhibited the powerful ability to recruit multiple immune cells. In contrast, SHED in a relatively high differentiation state (S1) may hold a solid ability to secret many factors with paracrine signaling capacity. The analysis result shows that SHED has more robust immunomodulatory properties than human bone marrow-derived mesenchymal stem cells (hBMSCs) or human umbilical cord-derived mesenchymal stem cells (hUCMSCs). When co-cultured with PBMCs, SHED can enhance the proliferation of Treg and down-regulate TNF-α in vitro. SHED may have some advantages in the treatment of inflammatory and autoimmune diseases.
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Affiliation(s)
- Yin Li
- Department of Stomatology, Beijing Jishuitan Hospital, Capital Medical University, Beijing, 100035, China.
- Beijing Engineering Research Center of Immunocellular Therapy, Beijing, China.
| | - Guangyuan Song
- Beijing Engineering Research Center of Immunocellular Therapy, Beijing, China
| | - Yu Jiang
- Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
- Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
| | - Haitao Zhao
- Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
| | - Yizhun Zhu
- School of Pharmacy, Human Phenome Institute, Fudan University, Shanghai, 201203, China
- State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China
| | - Shanshan Song
- Beijing Engineering Research Center of Immunocellular Therapy, Beijing, China
| | - Lulu Wang
- Beijing Engineering Research Center of Immunocellular Therapy, Beijing, China
| | - Xueying Wu
- Biomedical Innovation Center, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China.
- Beijing Key Laboratory for Therapeutic Cancer Vaccines, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China.
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Sun Z, Fukui M, Taketani S, Kako A, Kunieda S, Kakudo N. Predominant control of PDGF/PDGF receptor signaling in the migration and proliferation of human adipose‑derived stem cells under culture conditions with a combination of growth factors. Exp Ther Med 2024; 27:156. [PMID: 38476902 PMCID: PMC10928992 DOI: 10.3892/etm.2024.12444] [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: 09/25/2023] [Accepted: 01/19/2024] [Indexed: 03/14/2024] Open
Abstract
Human adipose-derived stem cells (hASCs) play important roles in regenerative medicine and tissue engineering. However, their clinical applications are limited because of their instability during cell culture. Platelet lysates (PLTs) contain large amounts of growth factors that are useful for manufacturing cellular products. Platelet-derived growth factor (PDGF) is a major growth factor in PLTs and a potent mitogen in hASCs. To optimize growth conditions, the effects of a combination of growth factors on the promotion of hASC proliferation were investigated. Moreover, PDGF-BB combined with vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) markedly enhanced the viability of hASCs compared with the effects of PDGF-BB alone. Neither VEGF nor HGF had any effect alone. All growth factor receptor inhibitors inhibited cell proliferation. Wound healing assays revealed that VEGF and HGF stimulated PDGF-dependent cell migration. The effects of these growth factors on the activation of their cognate receptors and signaling enzymes were assessed using immunoblotting. Phosphorylation of PDGF receptor (PDGFR)β, VEGF receptor (VEGFR)2 and MET proto-oncogene and receptor tyrosine kinase was induced by PDGF-BB treatment, and was further increased by treatment with PDGF-BB/VEGF and PDGF-BB/HGF. The levels of phospho-ERK1/2 and phospho-p38MAPK were increased by these treatments in parallel. Furthermore, the expression levels of SRY-box transcription factor 2 and peroxisome proliferator-activated receptor g were increased in PDGF-BB-treated cells, and PDGF-BB played a dominant role in spheroid formation. The findings of the present study highlighted that PDGF/PDGFR signaling played a predominant role in the proliferation and migration of hASCs, and suggested that PDGF was responsible for the efficacy of other growth factors when hASCs were cultured with PLTs.
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Affiliation(s)
- Zhongxin Sun
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Michika Fukui
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Shigeru Taketani
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Ayako Kako
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Sakurako Kunieda
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
| | - Natsuko Kakudo
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, Hirakata, Osaka 573-1010, Japan
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Choi N, Hwang J, Kim DY, Kim J, Song SY, Sung J. Involvement of DKK1 secreted from adipose-derived stem cells in alopecia areata. Cell Prolif 2024; 57:e13562. [PMID: 37991164 PMCID: PMC10905327 DOI: 10.1111/cpr.13562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 09/11/2023] [Accepted: 10/10/2023] [Indexed: 11/23/2023] Open
Abstract
Adipose-derived stem cells (ASCs) have shown efficacy in promoting hair growth, while DKK1 inhibits the WNT pathway, which is associated with hair loss. Our study focused on investigating the expression of DKK1 in alopecia areata (AA), a condition characterised by significant increases in the DKK1 levels in human and mouse ASCs. Treatment of interferon-γ increased the expression of DKK1 via STAT3 phosphorylation in ASCs. Treatment with recombinant DKK1 resulted in a decrease of cell growth in outer root sheath cells, whereas the use of a DKK1 neutralising antibody promoted hair growth. These results indicate that ASCs secrete DKK1, playing a crucial role in the progression and development of AA. Consequently, we generated DKK1 knockout (KO) ASCs using the Crispr/Cas9 system and evaluated their hair growth-promoting effects in an AA model. The DKK1 KO in ASCs led to enhanced cell motility and reduced cellular senescence by activating the WNT signalling pathway, while it reduced the expression of inflammatory cytokines by inactivating the NF-kB pathway. As expected, the intravenous injection of DKK1-KO-ASCs in AA mice, and the treatment with a conditioned medium derived from DKK1-KO-ASCs in hair organ culture proved to be more effective compared with the use of naïve ASCs and their conditioned medium. Overall, these findings suggest that DKK1 represents a novel therapeutic target for treating AA, and cell therapy using DKK1-KO-ASCs demonstrates greater efficiency.
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Affiliation(s)
| | | | - Doo Yeong Kim
- College of Pharmacy, Yonsei Institute of Pharmaceutical SciencesYonsei UniversityIncheonSouth Korea
| | - Jino Kim
- New Hair Plastic Surgery ClinicSeoulSouth Korea
| | - Seung Yong Song
- Institute for Human Tissue Restoration, Department of Plastic and Reconstructive SurgeryYonsei University College of MedicineSeoulSouth Korea
| | - Jong‐Hyuk Sung
- Epi Biotech Co., Ltd.IncheonSouth Korea
- College of Pharmacy, Yonsei Institute of Pharmaceutical SciencesYonsei UniversityIncheonSouth Korea
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Zheng M, Kim MH, Park SG, Kim WS, Oh SH, Sung JH. CXCL12 Neutralizing Antibody Promotes Hair Growth in Androgenic Alopecia and Alopecia Areata. Int J Mol Sci 2024; 25:1705. [PMID: 38338982 PMCID: PMC10855715 DOI: 10.3390/ijms25031705] [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: 12/21/2023] [Revised: 01/19/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
We had previously investigated the expression and functional role of C-X-C Motif Chemokine Ligand 12 (CXCL12) during the hair cycle progression. CXCL12 was highly expressed in stromal cells such as dermal fibroblasts (DFs) and inhibition of CXCL12 increased hair growth. Therefore, we further investigated whether a CXCL12 neutralizing antibody (αCXCL12) is effective for androgenic alopecia (AGA) and alopecia areata (AA) and studied the underlying molecular mechanism for treating these diseases. In the AGA model, CXCL12 is highly expressed in DFs. Subcutaneous (s.c.) injection of αCXCL12 significantly induced hair growth in AGA mice, and treatment with αCXCL12 attenuated the androgen-induced hair damage in hair organ culture. Androgens increased the secretion of CXCL12 from DFs through the androgen receptor (AR). Secreted CXCL12 from DFs increased the expression of the AR and C-X-C Motif Chemokine Receptor 4 (CXCR4) in dermal papilla cells (DPCs), which induced hair loss in AGA. Likewise, CXCL12 expression is increased in AA mice, while s.c. injection of αCXCL12 significantly inhibited hair loss in AA mice and reduced the number of CD8+, MHC-I+, and MHC-II+ cells in the skin. In addition, injection of αCXCL12 also prevented the onset of AA and reduced the number of CD8+ cells. Interferon-γ (IFNγ) treatment increased the secretion of CXCL12 from DFs through the signal transducer and activator of transcription 3 (STAT3) pathway, and αCXCL12 treatment protected the hair follicle from IFNγ in hair organ culture. Collectively, these results indicate that CXCL12 is involved in the progression of AGA and AA and antibody therapy for CXCL12 is promising for hair loss treatment.
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Affiliation(s)
- Mei Zheng
- Epi Biotech Co., Ltd., Incheon 21983, Republic of Korea; (M.Z.); (M.-H.K.)
| | - Min-Ho Kim
- Epi Biotech Co., Ltd., Incheon 21983, Republic of Korea; (M.Z.); (M.-H.K.)
| | - Sang-Gyu Park
- College of Pharmacy, Ajou University, Suwon 16499, Republic of Korea;
| | - Won-Serk Kim
- Department of Dermatology, School of Medicine, Sungkyunkwan University, Kangbuk Samsung Hospital, Seoul 03181, Republic of Korea;
| | - Sang-Ho Oh
- Department of Dermatology and Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea;
| | - Jong-Hyuk Sung
- Epi Biotech Co., Ltd., Incheon 21983, Republic of Korea; (M.Z.); (M.-H.K.)
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Fukui M, Lai F, Hihara M, Mitsui T, Matsuoka Y, Sun Z, Kunieda S, Taketani S, Odaka T, Okuma K, Kakudo N. Activation of cell adhesion and migration is an early event of platelet-rich plasma (PRP)-dependent stimulation of human adipose-derived stem/stromal cells. Hum Cell 2024; 37:181-192. [PMID: 37787969 DOI: 10.1007/s13577-023-00989-1] [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: 05/17/2023] [Accepted: 09/14/2023] [Indexed: 10/04/2023]
Abstract
Stem cell therapy is a promising treatment in regenerative medicine. Human adipose-derived stem/stromal cells (hASCs), a type of mesenchymal stem cell, are easy to harvest. In plastic and aesthetic surgery, hASC may be applied in the treatment of fat grafting, wound healing, and scar remodeling. Platelet-rich plasma (PRP) contains various growth factors, including platelet-derived growth factor (PDGF), which accelerates wound healing. We previously reported that PRP promotes the proliferation of hASC via multiple signaling pathways, and we evaluated the effect of PRP on the stimulation of hASC adhesion and migration, leading to the proliferation of these cells. When hASCs were treated with PRP, AKT, ERK1/2, paxillin and RhoA were rapidly activated. PRP treatment led to the formation of F-actin stress fibers. Strong signals for integrin β1, paxillin and RhoA at the cell periphery of RPR-treated cells indicated focal adhesion. PRP promoted cell adhesion and movement of hASC, compared with the control group. Imatinib, an inhibitor of the PDGF receptor tyrosine kinase, inhibited the promotion of PRP-dependent cell migration. PDGF treatment of hASCs also stimulated cell adhesion and migration but to a lesser extent than PRP treatment. PRP promoted the adhesion and the migration of hASC, mediated by the activation of AKT in the integrin signaling pathway. PRP treatment was more effective than PDGF treatment in enhancing cell migration. Thus, the ability of PRPs to promote migration of hASC to enhance cell growth is evident.
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Affiliation(s)
- Michika Fukui
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, 2-5-1, Hirakata, Osaka, 573-1010, Japan.
| | - Fangyuan Lai
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, 2-5-1, Hirakata, Osaka, 573-1010, Japan
| | - Masakatsu Hihara
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, 2-5-1, Hirakata, Osaka, 573-1010, Japan
| | - Toshihito Mitsui
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, 2-5-1, Hirakata, Osaka, 573-1010, Japan
| | - Yuki Matsuoka
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, 2-5-1, Hirakata, Osaka, 573-1010, Japan
| | - Zhongxin Sun
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, 2-5-1, Hirakata, Osaka, 573-1010, Japan
| | - Sakurako Kunieda
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, 2-5-1, Hirakata, Osaka, 573-1010, Japan
| | - Shigeru Taketani
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, 2-5-1, Hirakata, Osaka, 573-1010, Japan
| | - Tokifumi Odaka
- Department of Microbiology, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan
| | - Kazu Okuma
- Department of Microbiology, Kansai Medical University, Hirakata, Osaka, 573-1010, Japan
| | - Natsuko Kakudo
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, 2-5-1, Hirakata, Osaka, 573-1010, Japan
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Xue Z, Liao Y, Li Y. Effects of microenvironment and biological behavior on the paracrine function of stem cells. Genes Dis 2024; 11:135-147. [PMID: 37588208 PMCID: PMC10425798 DOI: 10.1016/j.gendis.2023.03.013] [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: 01/08/2023] [Revised: 02/14/2023] [Accepted: 03/05/2023] [Indexed: 08/18/2023] Open
Abstract
Mesenchymal stem cells (MSCs), the most well-studied cell type in the field of stem cell therapy, have multi-lineage differentiation and self-renewal potential. MSC-based therapies have been used to treat diverse diseases because of their ability to potently repair tissue and locally restore function. An increasing body of evidence demonstrates that paracrine function is central to the effects of MSC-based therapy. Growth factors, cytokines, chemokines, extracellular matrix components, and extracellular vehicles all contribute to the beneficial effects of MSCs on tissue regeneration and repair. The paracrine substances secreted by MSCs change depending on the tissue microenvironment and biological behavior. In this review, we discuss the bioactive substances secreted by MSCs depending on the microenvironment and biological behavior and their regulatory mechanisms, which explain their potential to treat human diseases, to provide new ideas for further research and clinical cell-free therapy.
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Affiliation(s)
- Zhixin Xue
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Yunjun Liao
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
| | - Ye Li
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China
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Lee HJ, Chae CW, Han HJ. Enhancing the therapeutic efficacy of mesenchymal stem cell transplantation in diabetes: Amelioration of mitochondrial dysfunction-induced senescence. Biomed Pharmacother 2023; 168:115759. [PMID: 37865993 DOI: 10.1016/j.biopha.2023.115759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/09/2023] [Accepted: 10/17/2023] [Indexed: 10/24/2023] Open
Abstract
Mesenchymal stem cell (MSC) transplantation offers significant potential for the treatment of diabetes mellitus (DM) and its complications. However, hyperglycemic conditions can induce senescence and dysfunction in both transplanted and resident MSCs, thereby limiting their therapeutic potential. Mitochondrial dysfunction and oxidative stress are key contributors to this process in MSCs exposed to hyperglycemia. As such, strategies aimed at mitigating mitochondrial dysfunction could enhance the therapeutic efficacy of MSC transplantation in DM. In this review, we provide an updated overview of how mitochondrial dysfunction mediates MSC senescence. We present experimental evidence for the molecular mechanisms behind high glucose-induced mitochondrial dysfunction in MSCs, which include impairment of mitochondrial biogenesis, mitochondrial calcium regulation, the mitochondrial antioxidant system, mitochondrial fusion-fission dynamics, mitophagy, and intercellular mitochondrial transfer. Furthermore, we propose potential pharmacological candidates that could improve the efficacy of MSC transplantation by enhancing mitochondrial function in patients with DM and related complications.
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Affiliation(s)
- Hyun Jik Lee
- Laboratory of Veterinary Physiology, College of Veterinary Medicine and Veterinary Medicine Center, Chungbuk National University, Cheongju 28644, Republic of South Korea; Institute for Stem Cell & Regenerative Medicine (ISCRM), Chungbuk National University, Cheongju 28644, Republic of South Korea
| | - Chang Woo Chae
- Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 Four Future Veterinary Medicine Leading Education & Research Center, Seoul National University, Seoul 08826, Republic of Korea
| | - Ho Jae Han
- Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science, and BK21 Four Future Veterinary Medicine Leading Education & Research Center, Seoul National University, Seoul 08826, Republic of Korea.
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11
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Wang Q, Zhou M, Zhang H, Hou Z, Liu D. Hypoxia Treatment of Adipose Mesenchymal Stem Cells Promotes the Growth of Dermal Papilla Cells via HIF-1α and ERK1/2 Signaling Pathways. Int J Mol Sci 2023; 24:11198. [PMID: 37446376 DOI: 10.3390/ijms241311198] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 06/25/2023] [Accepted: 06/30/2023] [Indexed: 07/15/2023] Open
Abstract
Dermal papilla cells (DPCs) cultured in vitro induce hair follicle formation. Using a hypoxic microenvironment to culture adipose mesenchymal stem cells (ADSCs) can promote hair follicle growth. However, the exact molecular mechanisms underlying this process remain unclear. In this study, ADSCs and DPCs from Arbas Cashmere goats were used. A hypoxic microenvironment promoted the proliferation of ADSCs and increased the pluripotency of ADSCs. The growth factors vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet-derived growth factor (PDGF) were upregulated in ADSCs in the hypoxia-conditioned medium (Hypo-cm). Hypo-cm also enhanced the ability of DPCs to induce hair follicle formation. Inhibitors of the ERK1/2 signaling pathway caused the expressions of growth factors that increased in hypoxic microenvironments to decrease; moreover, hypoxia-inducible factor-1α (HIF-1α) increased the expression levels of VEGF, bFGF, and PDGF and inhibited the expression of bone morphogenic protein 7 (BMP7). In conclusion, these findings improve the theoretical basis for the development of gene therapy drugs for the treatment of alopecia areata and hair thinning.
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Affiliation(s)
- Qing Wang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010021, China
| | - Mei Zhou
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010021, China
| | - Hongyan Zhang
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010021, China
| | - Zhuang Hou
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010021, China
| | - Dongjun Liu
- State Key Laboratory of Reproductive Regulation & Breeding of Grassland Livestock, Inner Mongolia University, Hohhot 010021, China
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12
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Jeon SH, Kim H, Sung JH. Hypoxia enhances the hair growth-promoting effects of embryonic stem cell-derived mesenchymal stem cells via NADPH oxidase 4. Biomed Pharmacother 2023; 159:114303. [PMID: 36706635 DOI: 10.1016/j.biopha.2023.114303] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 01/16/2023] [Accepted: 01/22/2023] [Indexed: 01/27/2023] Open
Abstract
Human embryonic stem cell (hES)-derived mesenchymal stem cells (-MSCs) are an unlimited source of MSCs. The hair growth-promoting effects of diverse MSCs have been reported, but not that of hES-MSCs. In the present study, we investigated the hair growth-promoting effects of hES-MSCs and their underlying mechanisms. hES-MSCs or conditioned medium of hES-MSCs exhibited hair-growth effects, which increased the length of mouse vibrissae and human hair follicles. hES-MSCs accelerated the telogen-to-anagen transition in C3H mice and were more effective than adipose-derived stem cells. We further examined whether hypoxia could enhance the hair-growth promoting effects of hES-MSCs. The injection of hES-MSCs or conditioned medium (Hyp-CM) cultured under hypoxia (2% O2) enhanced the telogen-to-anagen transition in C3H mice. Additionally, Hyp-CM increased the length of mouse vibrissae, human hair follicles, and the proliferation of human dermal papilla and outer root sheath cells. Moreover, fibroblast growth factor 7, interleukin 12B, and teratocarcinoma-derived growth factor 1 were upregulated under hypoxia, and the co-treatment with these three proteins increased the hair length and induced telogen-to-anagen transition. Hypoxia increased reactive oxygen species (ROS) production, and ROS scavenging attenuated the secretion of growth factors. NADPH oxidase 4 was primarily expressed in hES-MSCs and generated ROS under hypoxia. Collectively, our results suggest that hES-MSCs exhibit hair-growth effects, which is enhanced by hypoxia.
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Affiliation(s)
- Seng-Ho Jeon
- Daewoong Pharmaceutical, South Korea; College of Pharmacy, Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea.
| | - Hyunju Kim
- Epi Biotech Co., Ltd. Incheon, South Korea.
| | - Jong-Hyuk Sung
- College of Pharmacy, Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea; Epi Biotech Co., Ltd. Incheon, South Korea.
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13
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Sung JH. Effective and economical cell therapy for hair regeneration. Biomed Pharmacother 2023; 157:113988. [PMID: 36370520 DOI: 10.1016/j.biopha.2022.113988] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 11/01/2022] [Accepted: 11/05/2022] [Indexed: 11/11/2022] Open
Abstract
We reviewed and summarized the latest reports on the characteristics of stem cells and follicular cells that are under development for hair loss treatment. Compared with conventional medicine, cell therapy could be effective in the long term with a single treatment while having mild adverse effects. Adipose-derived stem cells (ASCs) have the advantages of easy access and large isolation amount compared with dermal papilla cells (DPCs) and dermal sheath cup cells (DSCs), and promote hair growth through the paracrine effect. ASCs have a poor potential in hair neogenesis, therefore, methods to enhance trichogenecity of ASCs should be developed. DSCs can be isolated from the peribulbar dermal sheath cup, while having immune tolerance, and hair inductivity. Therefore, DSCs were first developed and finished the phase II clinical trial; however, the hair growth was not satisfactory. Considering that a single injection of DSCs is effective for at least 9 months in the clinical setting, they can be an alternative therapy for hair regeneration. Though DPCs are not yet studied in clinical trials, we should pay attention to DPCs, as hair loss is associated with gradual reduction of DPCs and DP cell numbers fluctuate over the hair cycle. DPCs could make new hair follicles with epidermal cells, and have an immunomodulatory function to enable allogeneic transplantation. In addition, we can expand large quantities of DPCs with hair inductivity using spheroid culture, hypoxia condition, and growth factor supplement. 'Off-the-shelf' DPC therapy could be effective and economical, and therefore promising for hair regeneration.
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Affiliation(s)
- Jong-Hyuk Sung
- Epi Biotech Co., Ltd., Incheon, South Korea; College of Pharmacy, Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea.
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14
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Romaniyanto FNU, Mahyudin F, Prakoeswa CRS, Notobroto HB, Tinduh D, Ausrin R, Rantam FA, Suroto H, Utomo DN, Rhatomy S. Adipose-Derived Stem Cells (ASCs) for Regeneration of Intervertebral Disc Degeneration: Review Article. STEM CELLS AND CLONING: ADVANCES AND APPLICATIONS 2022; 15:67-76. [DOI: 10.2147/sccaa.s379714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 09/08/2022] [Indexed: 11/05/2022]
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15
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Zheng M, Oh SH, Choi N, Choi YJ, Kim J, Sung JH. CXCL12 inhibits hair growth through CXCR4. Biomed Pharmacother 2022; 150:112996. [PMID: 35462338 DOI: 10.1016/j.biopha.2022.112996] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 04/12/2022] [Accepted: 04/17/2022] [Indexed: 11/26/2022] Open
Abstract
CXCL12 and its receptors, which are highly expressed in the skin, are associated with various cutaneous diseases, including androgenic alopecia. However, their expression and role during the hair cycle are unknown. This study aims to investigate the expression of CXCL12 and its receptor, CXCR4, in the vicinity of hair follicles and their effect on hair growth. CXCL12 was highly expressed in dermal fibroblasts (DFs) and its level was elevated throughout the catagen and telogen phases of the hair cycle. CXCR4 is expressed in the dermal papilla (DP) and outer root sheath (ORS). In hair organ culture, hair loss was induced by recombinant CXCL12 therapy, which delayed the telogen-to-anagen transition and decreased hair length. In contrast, the suppression of CXCL12 using a neutralizing antibody and siRNA triggered the telogen-to-anagen transition and increased hair length in hair organ culture. Neutralization of CXCR7, one of the two receptors for CXCL12, only slightly affected hair growth. However, inhibition of CXCR4, the other receptor for CXCL12, increased hair growth to a considerable extent. In addition, in hair organ culture, the conditioned medium from DFs with CXCL12 siRNA considerably increased the hair length and induced proliferation of DP and ORS cells. CXCL12, through CXCR4 activation, increased STAT3 and STAT5 phosphorylation in DP and ORS cells. In contrast, blocking CXCL12 and CXCR4 decreased the phosphorylation of STAT3 and STAT5. In summary, these findings suggest that CXCL12 inhibits hair growth via the CXCR4/STAT signaling pathway and that CXCL12/CXCR4 pathway inhibitors are a promising treatment option for hair growth.
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Affiliation(s)
- Mei Zheng
- Epi Biotech Co., Ltd., Incheon 21983, South Korea
| | - Sang Ho Oh
- Department of Dermatology and Cutaneous Biology Research Institute, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, South Korea
| | - Nahyun Choi
- Epi Biotech Co., Ltd., Incheon 21983, South Korea
| | | | - Jino Kim
- New Hair Institute, Seoul 06134, South Korea
| | - Jong-Hyuk Sung
- Epi Biotech Co., Ltd., Incheon 21983, South Korea; College of Pharmacy, Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, South Korea.
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16
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Tian Y, Zhan Y, Jiang Q, Lu W, Li X. Expression and function of PDGF-C in development and stem cells. Open Biol 2021; 11:210268. [PMID: 34847773 PMCID: PMC8633783 DOI: 10.1098/rsob.210268] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Platelet-derived growth factor C (PDGF-C) is a relatively new member of the PDGF family, discovered nearly 20 years after the finding of platelet-derived growth factor A (PDGF-A) and platelet-derived growth factor B (PDGF-B). PDGF-C is generally expressed in most organs and cell types. Studies from the past 20 years have demonstrated critical roles of PDGF-C in numerous biological, physiological and pathological processes, such as development, angiogenesis, tumour growth, tissue remodelling, wound healing, atherosclerosis, fibrosis, stem/progenitor cell regulation and metabolism. Understanding PDGF-C expression and activities thus will be of great importance to various research disciplines. In this review, however, we mainly discuss the expression and functions of PDGF-C and its receptors in development and stem cells.
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Affiliation(s)
- Yi Tian
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, People’s Republic of China
| | - Ying Zhan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, People’s Republic of China
| | - Qin Jiang
- Ophthalmic Department, Affiliated Eye Hospital of Nanjing Medical University, Nanjing, People's Republic of China
| | - Weisi Lu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, People’s Republic of China
| | - Xuri Li
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, People’s Republic of China
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17
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Huang TT, Sun WJ, Liu HY, Ma HL, Cui BX. p66Shc-mediated oxidative stress is involved in gestational diabetes mellitus. World J Diabetes 2021; 12:1894-1907. [PMID: 34888014 PMCID: PMC8613666 DOI: 10.4239/wjd.v12.i11.1894] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/29/2021] [Accepted: 09/19/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is associated with a heightened level of oxidative stress, which is characterized by the overproduction of reactive oxygen species (ROS) from mitochondria. Previous studies showed that mitochondrial dysfunction is regulated by dynamin-related protein 1 (Drp1) and p66Shc in GDM.
AIM The aim was to investigate the expression of Drp1 and p66Shc and their possible mechanisms in the pathogenesis of GDM.
METHODS A total of 30 pregnant women, 15 with GDM and 15 without GDM, were enrolled. Peripheral blood mononuclear cells and placental tissue were collected. The human JEG3 trophoblast cell line was cultivated in 5.5 mmol/L or 30 mmol/L glucose and transfected with wild-type (wt)-p66Shc and p66Shc siRNA. P66Shc and Drp1 mRNA levels were detected by quantitative real-time polymerase chain reaction. The expression of p66Shc and Drp1 was assayed by immunohistochemistry and western blotting. ROS was assayed by dihydroethidium staining.
RESULTS The p66Shc mRNA level was increased in the serum (P < 0.01) and placentas (P < 0.01) of women with GDM, and the expression of Drp1 mRNA and protein were also increased in placentas (P < 0.05). In JEG3 cells treated with 30 mmol/L glucose, the mRNA and protein expression of p66Shc and Drp1 were increased at 24 h (both P < 0.05), 48 h (both P < 0.01) and 72 h (both P < 0.001). ROS expression was also increased. High levels of Drp1 and ROS expression were detected in JEG3 cells transfected with wt-p66Shc (P < 0.01), and low levels were detected in JEG3 cells transfected with p66Shc siRNA (P < 0.05).
CONCLUSION The upregulated expression of Drp1 and p66shc may contribute to the occurrence and development of GDM. Regulation of the mitochondrial fusion-fission balance could be a novel strategy for GDM treatment.
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Affiliation(s)
- Ting-Ting Huang
- Cheeloo College of Medicine, Shandong University, Jinan 250000, Shandong Province, China
- Department of Obstetrics, Taian City Central Hospital, Taian 271000, Shandong Province, China
| | - Wen-Juan Sun
- Department of Obstetrics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250000, Shandong Province, China
| | - Hai-Ying Liu
- Department of Obstetrics and Gynecology, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao 266000, Shandong Province, China
| | - Hong-Li Ma
- Department of Obstetrics, Taian City Central Hospital, Taian 271000, Shandong Province, China
| | - Bao-Xia Cui
- Department of Obstetrics and Gynecology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250013, Shandong Province, China
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18
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Deptuła M, Brzezicka A, Skoniecka A, Zieliński J, Pikuła M. Adipose-derived stromal cells for nonhealing wounds: Emerging opportunities and challenges. Med Res Rev 2021; 41:2130-2171. [PMID: 33522005 PMCID: PMC8247932 DOI: 10.1002/med.21789] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Revised: 12/30/2020] [Accepted: 01/20/2021] [Indexed: 12/21/2022]
Abstract
Wound healing complications affect thousands of people each year, thus constituting a profound economic and medical burden. Chronic wounds are a highly complex problem that usually affects elderly patients as well as patients with comorbidities such as diabetes, cancer (surgery, radiotherapy/chemotherapy) or autoimmune diseases. Currently available methods of their treatment are not fully effective, so new solutions are constantly being sought. Cell-based therapies seem to have great potential for use in stimulating wound healing. In recent years, much effort has been focused on characterizing of adipose-derived mesenchymal stromal cells (AD-MSCs) and evaluating their clinical use in regenerative medicine and other medical fields. These cells are easily obtained in large amounts from adipose tissue and show a high proregenerative potential, mainly through paracrine activities. In this review, the process of healing acute and nonhealing (chronic) wounds is detailed, with a special attention paid to the wounds of patients with diabetes and cancer. In addition, the methods and technical aspects of AD-MSCs isolation, culture and transplantation in chronic wounds are described, and the characteristics, genetic stability and role of AD-MSCs in wound healing are also summarized. The biological properties of AD-MSCs isolated from subcutaneous and visceral adipose tissue are compared. Additionally, methods to increase their therapeutic potential as well as factors that may affect their biological functions are summarized. Finally, their therapeutic potential in the treatment of diabetic and oncological wounds is also discussed.
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Affiliation(s)
- Milena Deptuła
- Laboratory of Tissue Engineering and Regenerative Medicine, Department of EmbryologyMedical University of GdanskGdańskPoland
| | | | - Aneta Skoniecka
- Department of Embryology, Faculty of MedicineMedical University of GdanskGdańskPoland
| | - Jacek Zieliński
- Department of Oncologic SurgeryMedical University of GdanskGdańskPoland
| | - Michał Pikuła
- Laboratory of Tissue Engineering and Regenerative Medicine, Department of EmbryologyMedical University of GdanskGdańskPoland
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19
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Zheng M, Choi N, Balboni G, Xia Y, Sung JH. Hair Growth Promotion by δ-Opioid Receptor Activation. Biomol Ther (Seoul) 2021; 29:643-649. [PMID: 34148869 PMCID: PMC8551727 DOI: 10.4062/biomolther.2021.064] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/24/2021] [Accepted: 05/26/2021] [Indexed: 11/05/2022] Open
Abstract
Literature has revealed that the delta opioid receptor (DOR) exhibited diverse pharmacological effects on neuron and skin. In the present study, we have investigated whether the activation of DOR has hair-growth promotion effects. Compared with other opioid receptor, DOR was highly expressed in epidermal component of hair follicle in human and rodents. The expression of DOR was high in the anagen phase, but it was low in the catagen and telogen phases during mouse hair cycle. Topical application of UFP-512, a specific DOR agonist, significantly accelerated the induction of the anagen in C3H mice. Topical application of UFP-512 also increased the hair length in hair organ cultures and promoted the proliferation and the migration of outer root sheath (ORS) cells. Similarly, pharmacological inhibition of DOR by naltrindole significantly inhibited the anagen transition process and decreased hair length in hair organ cultures. Thus, we further examined whether Wnt/β-catenin pathway was related to the effects of DOR on hair growth. We found that Wnt/β-catenin pathway was activated by UFP-512 and siRNA for β-catenin attenuated the UFP-512 induced proliferation and migration of ORS cells. Collectively, result established that DOR was involved in hair cycle regulation, and that DOR agonists such as UFP-512 should be developed for novel hair-loss treatment.
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Affiliation(s)
- Mei Zheng
- STEMORE Co. Ltd., Incheon 21983, Republic of Korea
| | - Nahyun Choi
- STEMORE Co. Ltd., Incheon 21983, Republic of Korea
| | - Gianfranco Balboni
- Department of Life and Environment Sciences, University of Cagliari, Cagliari 09124, Italy
| | - Ying Xia
- Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Fudan University, Shanghai 200032, China
| | - Jong-Hyuk Sung
- STEMORE Co. Ltd., Incheon 21983, Republic of Korea.,College of Pharmacy, Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Republic of Korea
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20
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Ahn H, Lee SY, Jung WJ, Lee KH. Alopecia treatment using minimally manipulated human umbilical cord-derived mesenchymal stem cells: Three case reports and review of literature. World J Clin Cases 2021; 9:3741-3751. [PMID: 34046478 PMCID: PMC8130094 DOI: 10.12998/wjcc.v9.i15.3741] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/24/2021] [Accepted: 03/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Alopecia areata (AA) is a common autoimmune disease characterized by hair loss. AA appears in extensive forms, such as progressive and diffusing hair loss (diffuse AA), a total loss of scalp hair (alopecia totalis), and complete loss of hair over the entire body (alopecia universalis). Recently, mesenchymal stem cells (MSCs) have been identified as a therapeutic alternative for autoimmune diseases. For this reason, preclinical and case studies of AA and related diseases using MSCs have been conducted.
CASE SUMMARY Case 1: A 55-year-old woman suffered from AA in two areas of the scalp. She was given 15 rounds of minimally manipulated umbilical cord-MSCs (MM-UC-MSCs) over 6 mo. The AA gradually improved 3 mo after the first round. The patient was cured, and AA did not recur. Case 2: A 30-year-old woman, with history of local steroid hormone injections, suffered from AA in one area on the scalp. She was given two rounds of MM-UC-MSCs over 1 mo. The AA immediately improved after the first round. The patient was cured, and AA did not recur. Case 3: A 20-year-old woman, who was diagnosed with alopecia universalis at the age of 12, was given 14 rounds of MM-UC-MSCs over 12 mo. Her hair began to grow about 3 mo after the first round. The patient was cured, and alopecia universalis did not recur.
CONCLUSION MM-UC-MSC transplantation potentially treats patients who suffer from AA and related diseases.
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Affiliation(s)
- Hyunjun Ahn
- bio Beauty&Health Company (bBHC) - Stem Cell Treatment & Research Institute (STRI), Seoul 04420, South Korea
- Department of Functional Genomics, University of Science and Technology KRIBB School, Deajeon 34113, South Korea
| | - Sang Yeon Lee
- bio Beauty&Health Company (bBHC) - Stem Cell Treatment & Research Institute (STRI), Seoul 04420, South Korea
| | - Won Ju Jung
- 97.7 Beauty&Health (B&H) Clinics, Seoul 04420, South Korea
| | - Kye-Ho Lee
- bio Beauty&Health Company (bBHC) - Stem Cell Treatment & Research Institute (STRI), Seoul 04420, South Korea
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21
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Zheng M, Choi N, Jang Y, Kwak DE, Kim Y, Kim WS, Oh SH, Sung JH. Hair growth promotion by necrostatin-1s. Sci Rep 2020; 10:17622. [PMID: 33077863 PMCID: PMC7573580 DOI: 10.1038/s41598-020-74796-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 09/25/2020] [Indexed: 11/09/2022] Open
Abstract
Necrostatins (Necs) have been developed as a receptor-interacting protein kinase 1 (RIPK1) inhibitor, thus inhibiting necroptosis. In this current study, we have investigated the possible involvement of necroptosis in the hair cycle regulation and further examined its underlying molecular mechanisms. Diverse RIPK1/3 inhibitors and siRNA were tested in the human outer-root sheath (ORS) cells and animal models. The expression and hair cycle-dependent expression of RIPK 1, respectively, were investigated in the hair follicles (HF) of human, pig, and the mouse. Resulting from the experiment, Nec-1s was most effective in the hair growth promotion among several inhibitors. Nec-1s induced the ORS cell proliferation and migration, and increased the HF length in mouse and pig organ cultures. In addition, it accelerated the telogen-to-anagen transition and elongated the anagen period in the mouse model. Both apoptosis and necroptosis were detected in hair cycle. RIPK1 and RIPK3 were highly expressed in ORS cells during the hair regression period. Nec-1s upregulated the mRNA expression of Wnt3a and Wnt5b, and the activity of β-catenin. Collectively, Nec-1s promotes hair growth through inhibiting necroptosis and activating the Wnt/β-catenin pathway. Necroptosis is involved in hair cycle regression, and Nec-1s is a promising target for hair-loss treatment.
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Affiliation(s)
- Mei Zheng
- STEMORE Co. Ltd, Incheon, South Korea
| | | | | | - Da Eun Kwak
- College of Pharmacy, Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahakro, Yeonsu-gu, Incheon, 21983, South Korea
| | - YoungSoo Kim
- College of Pharmacy, Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahakro, Yeonsu-gu, Incheon, 21983, South Korea
| | - Won-Serk Kim
- Department of Dermatology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, 03181, South Korea
| | - Sang Ho Oh
- Department of Dermatology, Severance Hospital and Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, 03722, South Korea
| | - Jong-Hyuk Sung
- College of Pharmacy, Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahakro, Yeonsu-gu, Incheon, 21983, South Korea.
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22
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Ren L, Chen X, Chen X, Li J, Cheng B, Xia J. Mitochondrial Dynamics: Fission and Fusion in Fate Determination of Mesenchymal Stem Cells. Front Cell Dev Biol 2020; 8:580070. [PMID: 33178694 PMCID: PMC7593605 DOI: 10.3389/fcell.2020.580070] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Accepted: 09/24/2020] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are pivotal to tissue homeostasis, repair, and regeneration due to their potential for self-renewal, multilineage differentiation, and immune modulation. Mitochondria are highly dynamic organelles that maintain their morphology via continuous fission and fusion, also known as mitochondrial dynamics. MSCs undergo specific mitochondrial dynamics during proliferation, migration, differentiation, apoptosis, or aging. Emerging evidence suggests that mitochondrial dynamics are key contributors to stem cell fate determination. The coordination of mitochondrial fission and fusion is crucial for cellular function and stress responses, while abnormal fission and/or fusion causes MSC dysfunction. This review focuses on the role of mitochondrial dynamics in MSC commitment under physiological and stress conditions. We highlight mechanistic insights into modulating mitochondrial dynamics and mitochondrial strategies for stem cell-based regenerative medicine. These findings shed light on the contribution of mitochondrial dynamics to MSC fate and MSC-based tissue repair.
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Affiliation(s)
- Lin Ren
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Xiaodan Chen
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Xiaobing Chen
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Jiayan Li
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Bin Cheng
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Juan Xia
- Hospital of Stomatology, Sun Yat-sen University, Guangzhou, China.,Guangdong Provincial Key Laboratory of Stomatology, Guangzhou, China.,Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
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23
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Choi N, Kim W, Oh SH, Sung J. Epiregulin promotes hair growth via EGFR-medicated epidermal and ErbB4-mediated dermal stimulation. Cell Prolif 2020; 53:e12881. [PMID: 32700456 PMCID: PMC7503099 DOI: 10.1111/cpr.12881] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/14/2020] [Accepted: 07/04/2020] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVES EREG (epiregulin), a member of the epidermal growth factor (EGF) family, plays a role in inflammation, wound healing, normal physiology and malignancies. However, little is known about its function on hair growth. MATERIALS AND METHODS Cell growth assay, QPCR and immunostaining were carried out. Telogen-to-anagen transition and organ culture were conducted. ROS level was monitored by staining DCFDA. RESULTS We investigated the hair inductive effect of EREG and the mechanism of stimulation on DPCs and ORS cells during hair cycling. Whereas EREG promoted hair growth, EREG knockdown inhibited hair growth as evidenced by telogen-to-anagen transition and organ culture models. EREG was expressed in epidermal cells including ORS cells in vivo. EREG activated phospho-ErbB4 in DPCs during hair cycling and stimulated DPCs via ErbB4 activation in vitro. In terms of the underlying mechanism, reactive oxygen species (ROS) played a key role in DPC stimulation. EREG also activated phospho-EGF receptor (EGFR) in epidermal cells including matrix and ORS cells in vivo and stimulated ORS cells via EGFR activation in vitro. CONCLUSIONS EREG, which is released from ORS cells, activated EGFR and ErbB4 on epidermal cells and DPCs during hair cycling, respectively. As a result, EREG stimulated epidermal cells a positive feedback and DPCs via regulating ROS generation for hair growth. Therefore, EREG therapy may be a novel solution for hair loss treatment.
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Affiliation(s)
- Nahyun Choi
- STEMORE Co. Ltd.IncheonSouth Korea
- College of PharmacyYonsei Institute of Pharmaceutical SciencesYonsei UniversityIncheonKorea
| | - Won‐Serk Kim
- Department of DermatologyKangbuk Samsung HospitalSungkyunkwan University School of MedicineSeoulSouth Korea
| | - Sang Ho Oh
- Department of DermatologySeverance Hospital and Cutaneous Biology Research InstituteYonsei University College of MedicineSeoulSouth Korea
| | - Jong‐Hyuk Sung
- STEMORE Co. Ltd.IncheonSouth Korea
- College of PharmacyYonsei Institute of Pharmaceutical SciencesYonsei UniversityIncheonKorea
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24
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Li Q, Lu Z, Jin M, Fei X, Quan K, Liu Y, Ma L, Chu M, Wang H, Wei C. Verification and Analysis of Sheep Tail Type-Associated PDGF-D Gene Polymorphisms. Animals (Basel) 2020; 10:ani10010089. [PMID: 31935823 PMCID: PMC7022463 DOI: 10.3390/ani10010089] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 12/25/2019] [Accepted: 12/29/2019] [Indexed: 12/12/2022] Open
Abstract
Simple Summary PDGF-D can be considered a candidate gene for selection for sheep tail type. This study investigated genetic variation of the PDGF-D gene in sheep with different tail types verified at a cellular level and revealed the molecular mechanism of PDGF-D in sheep tail fat deposition. We detected a total of two SNPs among 533 sheep. g.4122606 C > G site was significantly correlated with tail length, and g.3852134 C > T site was significantly correlated with tail width. In addition, overexpression of PDGF-D in sheep preadipocytes can promote adipogenic differentiation. The PDGF-D gene may participate in sheep tail fat deposition and could be used for molecular marker-assisted selection of sheep tail type. Abstract The aim of this study was to examine the correlation between the platelet-derived growth factor-D (PDGF-D) gene and sheep tail type character and explore the potential underlying mechanism. A total of 533 sheep were included in this study. Polymorphic sites were examined by Pool-seq, and individual genotype identification and correlation analysis between tail type data were conducted using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF-MS) method. JASPART website was used to predict transcription factor binding sites in the promoter region with and without PDGF-D gene mutation. The effect of PDGF-D on adipogenic differentiation of sheep preadipocytes was investigated. Two single nucleotide polymorphism sites were identified: g.4122606 C > G site was significantly correlated with tail length, and g.3852134 C > T site was significantly correlated with tail width. g.3852134 C > T was located in the promoter region. Six transcription factor binding sites were eliminated after promoter mutation, and three new transcription factor binding sites appeared. Expression levels of peroxisome proliferator-activated receptor gamma (PPARγ) and lipoproteinlipase (LPL) were significantly up-regulated upon PDGF-D overexpression. Oil red O staining showed increased small and large oil drops in the PDGF-D overexpression group. Together these results indicate the PDGF-D gene is an important gene controlling sheep tail shape and regulating sheep tail fat deposition to a certain degree.
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Affiliation(s)
- Qing Li
- Key Laboratory of Animal Genetics and Breeding and Reproduction of Ministry of Agriculture, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (Q.L.); (M.J.); (X.F.); (L.M.); (M.C.)
| | - Zengkui Lu
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China;
| | - Meilin Jin
- Key Laboratory of Animal Genetics and Breeding and Reproduction of Ministry of Agriculture, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (Q.L.); (M.J.); (X.F.); (L.M.); (M.C.)
| | - Xiaojuan Fei
- Key Laboratory of Animal Genetics and Breeding and Reproduction of Ministry of Agriculture, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (Q.L.); (M.J.); (X.F.); (L.M.); (M.C.)
| | - Kai Quan
- College of Animal Science and Technology, Henan University of Animal Husbandry and Economy, Zhengzhou 450046, China;
| | - Yongbin Liu
- Inner Mongolia Academy of Animal Husbandry Science, Hohhot 010031, China
| | - Lin Ma
- Key Laboratory of Animal Genetics and Breeding and Reproduction of Ministry of Agriculture, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (Q.L.); (M.J.); (X.F.); (L.M.); (M.C.)
| | - Mingxing Chu
- Key Laboratory of Animal Genetics and Breeding and Reproduction of Ministry of Agriculture, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (Q.L.); (M.J.); (X.F.); (L.M.); (M.C.)
| | - Huihua Wang
- Key Laboratory of Animal Genetics and Breeding and Reproduction of Ministry of Agriculture, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (Q.L.); (M.J.); (X.F.); (L.M.); (M.C.)
- Correspondence: (H.W.); (C.W.)
| | - Caihong Wei
- Key Laboratory of Animal Genetics and Breeding and Reproduction of Ministry of Agriculture, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China; (Q.L.); (M.J.); (X.F.); (L.M.); (M.C.)
- Correspondence: (H.W.); (C.W.)
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25
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Deng R, Liu Y, He H, Zhang H, Zhao C, Cui Z, Hong Y, Li X, Lin F, Yuan D, Liang X, Zhang Y. Haemin pre-treatment augments the cardiac protection of mesenchymal stem cells by inhibiting mitochondrial fission and improving survival. J Cell Mol Med 2020; 24:431-440. [PMID: 31660694 PMCID: PMC6933414 DOI: 10.1111/jcmm.14747] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 08/11/2019] [Accepted: 09/13/2019] [Indexed: 02/06/2023] Open
Abstract
The cardiac protection of mesenchymal stem cell (MSC) transplantation for myocardial infarction (MI) is largely hampered by low cell survival. Haem oxygenase 1 (HO-1) plays a critical role in regulation of cell survival under many stress conditions. This study aimed to investigate whether pre-treatment with haemin, a potent HO-1 inducer, would promote the survival of MSCs under serum deprivation and hypoxia (SD/H) and enhance the cardioprotective effects of MSCs in MI. Bone marrow (BM)-MSCs were pretreated with or without haemin and then exposed to SD/H. The mitochondrial morphology of MSCs was determined by MitoTracker staining. BM-MSCs and haemin-pretreated BM-MSCs were transplanted into the peri-infarct region in MI mice. SD/H induced mitochondrial fragmentation, as shown by increased mitochondrial fission and apoptosis of BM-MSCs. Pre-treatment with haemin greatly inhibited SD/H-induced mitochondrial fragmentation and apoptosis of BM-MSCs. These effects were partially abrogated by knocking down HO-1. At 4 weeks after transplantation, compared with BM-MSCs, haemin-pretreated BM-MSCs had greatly improved the heart function of mice with MI. These cardioprotective effects were associated with increased cell survival, decreased cardiomyocytes apoptosis and enhanced angiogenesis. Collectively, our study identifies haemin as a regulator of MSC survival and suggests a novel strategy for improving MSC-based therapy for MI.
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Affiliation(s)
- Rui Deng
- Department of General SurgeryThe Second Affiliated Hospital of Bengbu Medical CollegeBengbuChina
| | - Yaming Liu
- School of PharmacyBengbu Medical CollegeBengbuChina
| | - Haiwei He
- Department of Emergency MedicineGuangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
| | - Hao Zhang
- School of PharmacyBengbu Medical CollegeBengbuChina
| | - Chenling Zhao
- Department of Respiratory Medicinethe First Affiliated Hospital of Bengbu Medical CollegeBengbuChina
| | - Zhen Cui
- Department of Radiation Oncologythe First Affiliated Hospital of Bengbu Medical CollegeBengbuChina
| | - Yimei Hong
- Department of Emergency MedicineGuangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
| | - Xin Li
- Department of Emergency MedicineGuangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
| | - Fang Lin
- Clinical Translational Medical Research CenterShanghai East HospitalTongji University School of MedicineShanghaiChina
| | - Dongsheng Yuan
- Clinical Translational Medical Research CenterShanghai East HospitalTongji University School of MedicineShanghaiChina
| | - Xiaoting Liang
- Clinical Translational Medical Research CenterShanghai East HospitalTongji University School of MedicineShanghaiChina
| | - Yuelin Zhang
- School of PharmacyBengbu Medical CollegeBengbuChina
- Department of Emergency MedicineGuangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
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26
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HB-EGF Improves the Hair Regenerative Potential of Adipose-Derived Stem Cells via ROS Generation and Hck Phosphorylation. Int J Mol Sci 2019; 21:ijms21010122. [PMID: 31878047 PMCID: PMC6981845 DOI: 10.3390/ijms21010122] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Revised: 12/18/2019] [Accepted: 12/18/2019] [Indexed: 02/06/2023] Open
Abstract
Although adipose-derived stem cells (ASCs) have hair regenerative potential, their hair inductive capabilities are limited. The mitogenic and hair inductive effects of heparin binding-epidermal growth factor-like growth factor (HB-EGF) on ASCs were investigated in this study and the underlying mechanism of stimulation was examined. Cell growth, migration, and self-renewal assays, as well as quantitative polymerase chain reactions and immunostaining, were carried out. Telogen-to-anagen transition and organ culture using vibrissa follicles were also conducted. HB-EGF significantly increased ASC motility, including cell proliferation, migration, and self-renewal activity. The preconditioning of ASCs with HB-EGF induced telogen-to-anagen transition more rapidly in vivo, and injected PKH26-ASCs survived for longer periods of time. Conditioned medium obtained from HB-EGF-treated ASCs promoted hair growth in vivo, upregulating growth factors. In particular, thrombopoietin (THPO) also induced hair growth in vivo, stimulating dermal papilla cells (DPCs). Reactive oxygen species (ROS) appeared to play a key role in ASC stimulation as the inhibition of ROS generation and NOX4 knockout attenuated ASC stimulation and THPO upregulation by HB-EGF. In addition, the Hck phosphorylation pathway mediated the stimulation of ASCs by HB-EGF. In summary, HB-EGF increased the motility and paracrine effects of ASCs releasing THPO growth factor and THPO promoted hair growth-stimulating DPCs. ROS generation and Hck phosphorylation are key factors in HB-EGF-induced ASC stimulation. Therefore, combination therapy involving HB-EGF and ASCs may provide a novel solution for hair-loss treatment.
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27
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Choi N, Sung JH. Udenafil Induces the Hair Growth Effect of Adipose-Derived Stem Cells. Biomol Ther (Seoul) 2019; 27:404-413. [PMID: 30971059 PMCID: PMC6609107 DOI: 10.4062/biomolther.2018.195] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 01/01/2019] [Accepted: 02/25/2019] [Indexed: 12/25/2022] Open
Abstract
Udenafil, which is a PDE5 inhibitor, is used to treat erectile dysfunction. However, it is unclear whether udenafil induces hair growth via the stimulation of adipose-derived stem cells (ASCs). In this study, we investigated whether udenafil stimulates ASCs and whether increased growth factor secretion from ASCs to facilitate hair growth. We found that subcutaneous injection of udenafil-treated ASCs accelerated telogen-to-anagen transition in vivo. We also observed that udenafil induced proliferation, migration and tube formation of ASCs. It also increased the secretion of growth factors from ASCs, such as interleukin-4 (IL-4) and IL12B, and the phosphorylation of ERK1/2 and NFκB. Furthermore, concomitant upregulation of IL-4 and IL12B mRNA levels was attenuated by ERK inhibitor or NFκB knockdown. Application of IL-4 or IL12B enhanced anagen induction in mice and increased hair follicle length in organ culture. The results indicated that udenafil stimulates ASC motility and increases paracrine growth factor, including cytokine signaling. Udenafil-stimulated secretion of cytokine from ASCs may promote hair growth via the ERK and NFκB pathways. Therefore, udenafil can be used as an ASC-preconditioning agent for hair growth.
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Affiliation(s)
- Nahyun Choi
- College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea.,STEMORE Co. Ltd., Incheon 21984, Republic of Korea
| | - Jong-Hyuk Sung
- College of Pharmacy, Yonsei University, Incheon 21983, Republic of Korea.,STEMORE Co. Ltd., Incheon 21984, Republic of Korea
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28
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Li X, Ma T, Sun J, Shen M, Xue X, Chen Y, Zhang Z. Harnessing the secretome of adipose-derived stem cells in the treatment of ischemic heart diseases. Stem Cell Res Ther 2019; 10:196. [PMID: 31248452 PMCID: PMC6598280 DOI: 10.1186/s13287-019-1289-7] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Adipose-derived stem cells (ASCs) are promising therapeutic cells for ischemic heart diseases, due to the ease and efficiency of acquisition, the potential of myocardial lineage differentiation, and the paracrine effects. Recently, many researchers have claimed that the ASC-based myocardial repair is mainly attributed to its paracrine effects, including the anti-apoptosis, pro-angiogenesis, anti-inflammation effects, and the inhibition of fibrosis, rather than the direct differentiation into cardiovascular lineage cells. However, the usage of ASCs comes with the problems of low cardiac retention and survival after transplantation, like other stem cells, which compromises the effectiveness of the therapy. To overcome these drawbacks, researchers have proposed various strategies for improving survival rate and ensuring sustained paracrine secretion. They also investigated the safety and efficacy of phase I and II clinical trials of ASC-based therapy for cardiovascular diseases. In this review, we will discuss the characterization and paracrine effects of ASCs on myocardial repair, followed by the strategies for stimulating the paracrine secretion of ASCs, and finally their clinical usage.
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Affiliation(s)
- Xiaoting Li
- Department of Cardiology, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Road, Suzhou, 215004, China
| | - Teng Ma
- Department of Cardiovascular Surgery, The First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, No.899, Pinghai Road, Suzhou, 215006, China
| | - Jiacheng Sun
- Department of Cardiovascular Surgery, The First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, No.899, Pinghai Road, Suzhou, 215006, China
| | - Mingjing Shen
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Road, Suzhou, 215004, China
| | - Xiang Xue
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Road, Suzhou, 215004, China
| | - Yongbing Chen
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Road, Suzhou, 215004, China.
| | - Zhiwei Zhang
- Department of Cardiothoracic Surgery, The Second Affiliated Hospital of Soochow University, No.1055, Sanxiang Road, Suzhou, 215004, China.
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29
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Zheng M, Jang Y, Choi N, Kim DY, Han TW, Yeo JH, Lee J, Sung JH. Hypoxia improves hair inductivity of dermal papilla cells via nuclear NADPH oxidase 4-mediated reactive oxygen species generation'. Br J Dermatol 2019; 181:523-534. [PMID: 30703252 DOI: 10.1111/bjd.17706] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/24/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND Dermal papilla cells (DPCs) play a key role in hair regeneration and morphogenesis. Therefore, tremendous efforts have been made to promote DPC hair inductivity. OBJECTIVES The aim of this study was to investigate the mitogenic and hair inductive effects of hypoxia on DPCs and examine the underlying mechanism of hypoxia-induced stimulation of DPCs. METHODS DPCs' hair inductivity was examined under normoxia (20% O2 ) and hypoxia (2% O2 ). RESULTS Hypoxia significantly increased the proliferation and delayed senescence of DPCs via Akt phosphorylation and downstream pathways. Hypoxia upregulated growth factor secretion of DPCs through the mitogen-activated protein kinase pathway. Hypoxia-preconditioned DPCs induced the telogen-to-anagen transition in C3 H mice, and also enhanced hair neogenesis in a hair reconstitution assay. Injected green fluorescent protein-labelled DPCs migrated to the outer root sheath of the hair follicle, and hypoxia-preconditioning increased survival and migration of DPCs in vivo. Conditioned medium obtained from hypoxia increased the hair length of mouse vibrissa follicles via upregulation of alkaline phosphatase, vascular endothelial growth factor, and glial cell line-derived neurotrophic factor. We examined the mechanism of this hypoxia-induced stimulation, and found that reactive oxygen species (ROS) play a key role. For example, inhibition of ROS generation by N-acetylcysteine or diphenyleneiodonium treatment attenuated DPCs' hypoxia-induced stimulation, but treatment with ROS donors induced mitogenic effects and anagen transition. NADPH oxidase 4 is highly expressed in the DPC nuclear region, and NOX4 knockout by CRISPR-Cas9 attenuated the hypoxia-induced stimulation of DPCs. CONCLUSIONS Our results suggest that DPC culture under hypoxia has great advantages over normoxia, and is a novel solution for producing DPCs for cell therapy. What's already known about this topic? Dermal papilla cells (DPCs) play a key role in hair regeneration and morphogenesis, but they are difficult to isolate and expand for use in cell therapy. Tremendous efforts have been made to increase proliferation of DPCs and promote their hair formation ability. What does this study add? Hypoxia (2% O2 ) culture of DPCs increases proliferation, delays senescence and enhances hair inductivity of DPCs. Reactive oxygen species play a key role in hypoxia-induced stimulation of DPC. What is the translational message? Preconditioning DPCs under hypoxia improves their hair regenerative potential, and is a novel solution for producing DPCs for cell therapy to treat hair loss.
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Affiliation(s)
- M Zheng
- STEMORE Co. Ltd, Incheon, South Korea
| | - Y Jang
- STEMORE Co. Ltd, Incheon, South Korea
| | - N Choi
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea
| | - D Y Kim
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea
| | - T W Han
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea
| | - J H Yeo
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea
| | - J Lee
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea
| | - J-H Sung
- STEMORE Co. Ltd, Incheon, South Korea.,College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea
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30
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Marinaro F, Sánchez-Margallo FM, Álvarez V, López E, Tarazona R, Brun MV, Blázquez R, Casado JG. Meshes in a mess: Mesenchymal stem cell-based therapies for soft tissue reinforcement. Acta Biomater 2019; 85:60-74. [PMID: 30500445 DOI: 10.1016/j.actbio.2018.11.042] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 11/21/2018] [Accepted: 11/26/2018] [Indexed: 12/19/2022]
Abstract
Surgical meshes are frequently used for the treatment of abdominal hernias, pelvic organ prolapse, and stress urinary incontinence. Though these meshes are designed for tissue reinforcement, many complications have been reported. Both differentiated cell- and mesenchymal stem cell-based therapies have become attractive tools to improve their biocompatibility and tissue integration, minimizing adverse inflammatory reactions. However, current studies are highly heterogeneous, making it difficult to establish comparisons between cell types or cell coating methodologies. Moreover, only a few studies have been performed in clinically relevant animal models, leading to contradictory results. Finally, a thorough understanding of the biological mechanisms of mesenchymal stem cells in the context of foreign body reaction is lacking. This review aims to summarize in vitro and in vivo studies involving the use of differentiated and mesenchymal stem cells in combination with surgical meshes. According to preclinical and clinical studies and considering the therapeutic potential of mesenchymal stem cells, it is expected that these cells will become valuable tools in the treatment of pathologies requiring tissue reinforcement. STATEMENT OF SIGNIFICANCE: The implantation of surgical meshes is the standard procedure to reinforce tissue defects such as hernias. However, an adverse inflammatory response secondary to this implantation is frequently observed, leading to a strong discomfort and chronic pain in the patients. In many cases, an additional surgical intervention is needed to remove the mesh. Both differentiated cell- and stem cell-based therapies have become attractive tools to improve biocompatibility and tissue integration, minimizing adverse inflammatory reactions. However, current studies are incredibly heterogeneous and it is difficult to establish a comparison between cell types or cell coating methodologies. This review aims to summarize in vitro and in vivo studies where differentiated and stem cells have been combined with surgical meshes.
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Affiliation(s)
- F Marinaro
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, Ctra. N-521, km 41.8, 10071 Cáceres, Spain
| | - F M Sánchez-Margallo
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, Ctra. N-521, km 41.8, 10071 Cáceres, Spain; CIBER de Enfermedades Cardiovasculares, Avenida Monforte de Lemos, 3-5. Pabellón 11. Planta 0, 28029 Madrid, Spain
| | - V Álvarez
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, Ctra. N-521, km 41.8, 10071 Cáceres, Spain
| | - E López
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, Ctra. N-521, km 41.8, 10071 Cáceres, Spain
| | - R Tarazona
- Immunology Unit, Department of Physiology, University of Extremadura, 10071 Caceres, Spain
| | - M V Brun
- Department of Small Animal Medicine, Federal University of Santa Maria (UFSM), Av. Roraima, 1000 - 7 - Camobi, Santa Maria, 97105-900 Rio Grande do Sul, Brazil
| | - R Blázquez
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, Ctra. N-521, km 41.8, 10071 Cáceres, Spain; CIBER de Enfermedades Cardiovasculares, Avenida Monforte de Lemos, 3-5. Pabellón 11. Planta 0, 28029 Madrid, Spain.
| | - J G Casado
- Stem Cell Therapy Unit, Jesús Usón Minimally Invasive Surgery Centre, Ctra. N-521, km 41.8, 10071 Cáceres, Spain; CIBER de Enfermedades Cardiovasculares, Avenida Monforte de Lemos, 3-5. Pabellón 11. Planta 0, 28029 Madrid, Spain
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31
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Smith OJ, Jell G, Mosahebi A. The use of fat grafting and platelet-rich plasma for wound healing: A review of the current evidence. Int Wound J 2018; 16:275-285. [PMID: 30460739 DOI: 10.1111/iwj.13029] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Accepted: 10/16/2018] [Indexed: 12/17/2022] Open
Abstract
Fat grafting is becoming a common procedure in regenerative medicine because of its high content of growth factors and adipose derived stem cells (ADSCs) and the ease of harvest, safety, and low cost. The high concentration of ADSCs found in fat has the potential to differentiate into a wide range of wound-healing cells including fibroblasts and keratinocytes as well as demonstrating proangiogenic qualities. This suggests that fat could play an important role in wound healing. However retention rates of fat grafts are highly variable due in part to inconsistent vascularisation of the transplanted fat. Furthermore, conditions such as diabetes, which have a high prevalence of chronic wounds, reduce the potency and regenerative potential of ADSCs. Platelet-rich plasma (PRP) is an autologous blood product rich in growth factors, cell adhesion molecules, and cytokines. It has been hypothesised that PRP may have a positive effect on the survival and retention of fat grafts because of improved proliferation and differentiations of ADSCs, reduced inflammation, and improved vascularisation. There is also increasing interest in a possible synergistic effect that PRP may have on the healing potential of fat, although the evidence for this is very limited. In this review, we evaluate the evidence in both in vitro and animal studies on the mechanistic relationship between fat and PRP and how this translates to a benefit in wound healing. We also discuss future directions for both research and clinical practice on how to enhance the regenerative potential of the combination of PRP and fat.
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Affiliation(s)
- Oliver J Smith
- Department of Plastic Surgery, Royal Free Hospital, London, UK.,Division of Surgery and Interventional Science, University College London, London, UK
| | - Gavin Jell
- Division of Surgery and Interventional Science, University College London, London, UK
| | - Ash Mosahebi
- Department of Plastic Surgery, Royal Free Hospital, London, UK.,Division of Surgery and Interventional Science, University College London, London, UK
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32
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Choi N, Choi J, Kim JH, Jang Y, Yeo JH, Kang J, Song SY, Lee J, Sung JH. Generation of trichogenic adipose-derived stem cells by expression of three factors. J Dermatol Sci 2018; 92:18-29. [PMID: 30146106 DOI: 10.1016/j.jdermsci.2018.08.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 08/07/2018] [Accepted: 08/10/2018] [Indexed: 01/06/2023]
Abstract
BACKGROUND Previous studies demonstrated that adipose-derived stem cells (ASCs) can promote hair growth, but unmet needs exist for enhancing ASC hair inductivity. OBJECTIVE Therefore, we introduced three trichogenic factors platelet-derived growth factor-A, SOX2, and β-catenin to ASCs (tfASCs) and evaluated whether tfASCs have similar characteristics as dermal papilla (DP) cells. METHOD Global gene expression was examined using NGS analysis. Telogen-to-anagen induction, vibrissae hair follicle organ culture and patch assay were used. RESULTS tfASC cell size is smaller than that of ASCs, and they exhibit short doubling time. tfASCs also resist aging and can be expanded until passage 12. Cell proportion in S and G2/M increases in tfASCs, and tfASCs express high mRNA levels of cell cycle related genes. The mRNA expression of DP markers was notably higher in tfASCs. Moreover, NGS analysis revealed that the global gene expression of tfASCs is similar to that of DP cells. The injection of tfASCs accelerated the telogen-to-anagen transition and conditioned medium of tfASCs increased the anagen phase of vibrissal hair follicles. Finally, we found that the injection of 3D-cultured tfASCs at p 9 generated new hair follicles in nude mice. CONCLUSION Collectively, these results indicate that 1) tfASCs have similar characteristics as DP cells, 2) tfASCs have enhanced hair-regenerative potential compared with ASCs, and 3) tfASCs even at late passage can make new hair follicles in a hair reconstitution assay. Because DP cells are difficult to isolate/expand and ASCs have low hair inductivity, tfASCs and tfASC-CM are clinically good candidates for hair regeneration.
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Affiliation(s)
- Nahyun Choi
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea; STEMORE Co. Ltd., Incheon, South Korea
| | - Junjeong Choi
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea
| | | | | | - Joo Hye Yeo
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea
| | - Juwon Kang
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea
| | - Seung Yong Song
- Institute for Human Tissue Restoration, Department of Plastic and Reconstructive Surgery, Yonsei University College of Medicine, Seoul, South Korea
| | - Jinu Lee
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea.
| | - Jong-Hyuk Sung
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, South Korea; STEMORE Co. Ltd., Incheon, South Korea.
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Lu W, Li X. PDGFs and their receptors in vascular stem/progenitor cells: Functions and therapeutic potential in retinal vasculopathy. Mol Aspects Med 2018; 62:22-32. [DOI: 10.1016/j.mam.2017.10.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 10/04/2017] [Indexed: 02/07/2023]
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Periasamy R, Elshaer SL, Gangaraju R. CD140b (PDGFRβ) signaling in adipose-derived stem cells mediates angiogenic behavior of retinal endothelial cells. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2018; 5:1-9. [PMID: 30976657 DOI: 10.1007/s40883-018-0068-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Adipose-derived stem cells (ASCs) are multipotent mesenchymal progenitor cells that have functional and phenotypic overlap with pericytes lining microvessels in adipose tissue. The role of CD140b [platelet-derived growth factor receptor- β (PDGFR-β)], a constitutive marker expressed by ASCs, in the angiogenic behavior of human retinal endothelial cells (HREs) is not known. CD140b was knocked down in ASCs using targeted siRNA and lipofectamine transfection protocol. Both CD140b+ and CD140b- ASCs were tested for their proliferation (WST-1 reagent), adhesion (laminin-1 coated plates), and migration (wound-scratch assay). Angiogenic effect of CD140b+ and CD140b- ASCs on HREs was examined by co-culturing ASCs:HREs in 12:1 ratio for 6 days followed by visualization of vascular network by Isolectin B4 staining. The RayBio® Membrane-Based Antibody Array was used to assess differences in human cytokines released by CD140b+ or CD140b- ASCs. Knockdown of CD140b in ASCs resulted in a significant 50% decrease in proliferation rate, 25% decrease in adhesion ability to Laminin-1, and 50% decrease in migration rate, as compared to CD140b+ ASCs. Direct contact of ASCs expressing CD140b+ with HREs resulted in robust vascular network formation that was significantly reduced with using CD140b- ASCs. Of the 80 proteins tested, 45 proteins remained unchanged (>0.5-<1.5 fold), 6 proteins including IL-10 downregulated (<0.5 fold) and 29 proteins including IL-16 & TNF-β were upregulated (>1.5 fold) in CD140b- ASCs compared to CD140b+ ASCs. Our data demonstrate a substantial role for CD140b in the intrinsic abilities of ASCs and their angiogenic influence on HREs. Future studies are needed to fully explore the signaling of CD140b in ASCs in vivo for retinal regeneration.
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Affiliation(s)
- Ramesh Periasamy
- Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Sciences Center, Memphis, TN, 38163. USA
| | - Sally L Elshaer
- Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Sciences Center, Memphis, TN, 38163. USA
| | - Rajashekhar Gangaraju
- Department of Ophthalmology, Hamilton Eye Institute, University of Tennessee Health Sciences Center, Memphis, TN, 38163. USA.,Anatomy and neurobiology, University of Tennessee Health Sciences Center, Memphis, TN, 38163. USA
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Perturbations in mitochondrial dynamics by p66Shc lead to renal tubular oxidative injury in human diabetic nephropathy. Clin Sci (Lond) 2018; 132:1297-1314. [PMID: 29760122 DOI: 10.1042/cs20180005] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Revised: 04/30/2018] [Accepted: 05/14/2018] [Indexed: 12/26/2022]
Abstract
Renal tubular injury is increasingly being recognized as an early characteristic of diabetic nephropathy (DN). Mitochondrial dynamic alterations and redox protein p66Shc-mediated oxidative stress are both critical for ensuing diabetic tubular cell injury and apoptosis; whether these two processes are interlinked remains unclear. In the present study, we observed changes in mitochondrial morphology and expression of associated proteins in tubules of patients with DN. We demonstrated mitochondrial fragmentation as an important pathogenic feature of tubular cell injury that is linked to oxidative stress and p66Shc up-regulation. In renal proximal tubular cells, alterations in mitochondrial dynamics and expression of fission-fusion proteins were observed under high glucose (HG) ambience, along with p66Shc Ser36 phosphorylation. Gene ablation of p66Shc alleviated HG-induced mitochondrial fragmentation, down-regulated Fis1 and reduced p66Shc-Fis1 binding, increased Mfn1 expression, and disrupted interactions between Mfn1 and proapoptotic Bak. Overexpression of p66Shc exacerbated these changes, whereas overexpression of dominant-negative p66Shc Ser36 mutant had a marginal effect under HG, indicating that p66Shc phosphorylation as a prerequisite in the modulation of mitochondrial dynamics. Disrupted mitochondrial dynamics and enhanced Mfn1-Bak interactions modulated by p66Shc led to loss of mitochondrial voltage potential, cytochrome C release, excessive ROS generation, and apoptosis. Taken together, these results link p66Shc to mitochondrial dynamic alterations in the pathogenesis of DN and unveil a novel mechanism by which p66Shc mediates HG-induced mitochondrial fragmentation and proapoptotic signaling that results in oxidative injury and apoptosis in the tubular compartment in human diabetic nephropathy.
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Lai F, Kakudo N, Morimoto N, Taketani S, Hara T, Ogawa T, Kusumoto K. Platelet-rich plasma enhances the proliferation of human adipose stem cells through multiple signaling pathways. Stem Cell Res Ther 2018; 9:107. [PMID: 29661222 PMCID: PMC5902971 DOI: 10.1186/s13287-018-0851-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 03/18/2018] [Accepted: 03/20/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Platelet-rich plasma (PRP) is an autologous blood product that contains a high concentration of several growth factors. Platelet-derived growth factor (PDGF)-BB is a potential mitogen for human adipose-derived stem cells (hASCs). PRP stimulates proliferation of hASCs; however, the signaling pathways activated by PRP remain unclear. METHODS hASCs were cultured with or without PRP or PDGF-BB, and proliferation was assessed. hASCs were also treated with PRP or PDGF-BB with or without imatinib, which is a PDGF receptor tyrosine kinase inhibitor, or sorafenib, which is a multikinase inhibitor. Inhibition of cell proliferation was examined using anti-PDGF antibody (Abcam, Cambridge, UK), by cell counting. We assessed the effects of inhibitors of various protein kinases such as ERK1/2, JNK, p38, and Akt on the proliferation of hASCs. RESULTS The proliferation was remarkably promoted in cells treated with either 1% PRP or 10 ng/ml PDGF-BB, and both imatinib and sorafenib inhibited this proliferation. Anti-PDGF antibody (0.5 and 2 μg/ml) significantly decreased the proliferation of hASCs compared with control. PRP-mediated hASC proliferation was blocked by inhibitors of ERK1/2, Akt, and JNK, but not by an inhibitor of p38. CONCLUSIONS PRP promotes hASC proliferation, and PDGF-BB in PRP plays a major role in inducing the proliferation of hASCs. PRP promotes hASC proliferation via ERK1/2, PI3K/Akt, and JNK signaling pathways.
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Affiliation(s)
- Fangyuan Lai
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan
| | - Natsuko Kakudo
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan.
| | - Naoki Morimoto
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan
| | - Shigeru Taketani
- Department of Microbiology, Kansai Medical University, Osaka, 573-1010, Japan
| | - Tomoya Hara
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan.,Department of Oral Implantology, Osaka Dental University, Osaka, 573-1121, Japan
| | - Takeshi Ogawa
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan
| | - Kenji Kusumoto
- Department of Plastic and Reconstructive Surgery, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan
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Graziano ACE, Avola R, Perciavalle V, Nicoletti F, Cicala G, Coco M, Cardile V. Physiologically based microenvironment for in vitro neural differentiation of adipose-derived stem cells. World J Stem Cells 2018; 10:23-33. [PMID: 29588808 PMCID: PMC5867480 DOI: 10.4252/wjsc.v10.i3.23] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 03/20/2018] [Accepted: 03/21/2018] [Indexed: 02/06/2023] Open
Abstract
The limited capacity of nervous system to promote a spontaneous regeneration and the high rate of neurodegenerative diseases appearance are keys factors that stimulate researches both for defining the molecular mechanisms of pathophysiology and for evaluating putative strategies to induce neural tissue regeneration. In this latter aspect, the application of stem cells seems to be a promising approach, even if the control of their differentiation and the maintaining of a safe state of proliferation should be troubled. Here, we focus on adipose tissue-derived stem cells and we seek out the recent advances on the promotion of their neural differentiation, performing a critical integration of the basic biology and physiology of adipose tissue-derived stem cells with the functional modifications that the biophysical, biomechanical and biochemical microenvironment induces to cell phenotype. The pre-clinical studies showed that the neural differentiation by cell stimulation with growth factors benefits from the integration with biomaterials and biophysical interaction like microgravity. All these elements have been reported as furnisher of microenvironments with desirable biological, physical and mechanical properties. A critical review of current knowledge is here proposed, underscoring that a real advance toward a stable, safe and controllable adipose stem cells clinical application will derive from a synergic multidisciplinary approach that involves material engineer, basic cell biology, cell and tissue physiology.
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Affiliation(s)
| | - Rosanna Avola
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania 95123, Italy
| | - Vincenzo Perciavalle
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania 95123, Italy
| | - Ferdinando Nicoletti
- Department of Biomedical and Biotechnological Sciences, Section of Pathology and Oncology, University of Catania, Catania 95123, Italy
| | - Gianluca Cicala
- Department of Civil Engineering and Architecture, University of Catania, Catania 95125, Italy
| | - Marinella Coco
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania 95123, Italy
| | - Venera Cardile
- Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania 95123, Italy
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Wu YS, Zhu B, Luo AL, Yang L, Yang C. The Role of Cardiokines in Heart Diseases: Beneficial or Detrimental? BIOMED RESEARCH INTERNATIONAL 2018; 2018:8207058. [PMID: 29744364 PMCID: PMC5878913 DOI: 10.1155/2018/8207058] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 01/19/2018] [Accepted: 02/07/2018] [Indexed: 12/11/2022]
Abstract
Cardiovascular disease remains the leading cause of morbidity and mortality, imposing a major disease burden worldwide. Therefore, there is an urgent need to identify new therapeutic targets. Recently, the concept that the heart acts as a secretory organ has attracted increasing attention. Proteins secreted by the heart are called cardiokines, and they play a critical physiological role in maintaining heart homeostasis or responding to myocardial damage and thereby influence the development of heart diseases. Given the critical role of cardiokines in heart disease, they might represent a promising therapeutic target. This review will focus on several cardiokines and discuss their roles in the pathogenesis of heart diseases and as potential therapeutics.
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Affiliation(s)
- Ye-Shun Wu
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Bin Zhu
- Department of Critical Care Medicine, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Ai-Lin Luo
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
| | - Ling Yang
- Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, China
| | - Chun Yang
- Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China
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Minoxidil Promotes Hair Growth through Stimulation of Growth Factor Release from Adipose-Derived Stem Cells. Int J Mol Sci 2018; 19:ijms19030691. [PMID: 29495622 PMCID: PMC5877552 DOI: 10.3390/ijms19030691] [Citation(s) in RCA: 58] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 02/24/2018] [Accepted: 02/26/2018] [Indexed: 01/09/2023] Open
Abstract
Minoxidil directly promotes hair growth via the stimulation of dermal papilla (DP) and epithelial cells. Alternatively, there is little evidence for indirect promotion of hair growth via stimulation of adipose-derived stem cells (ASCs). We investigated whether minoxidil stimulates ASCs and if increased growth factor secretion by ASCs facilitates minoxidil-induced hair growth. Telogen-to-anagen induction was examined in mice. Cultured DP cells and vibrissae hair follicle organ cultures were used to further examine the underlying mechanisms. Subcutaneous injection of minoxidil-treated ASCs accelerated telogen-to-anagen transition in mice, and increased hair weight at day 14 post-injection. Minoxidil did not alter ASC proliferation, but increased migration and tube formation. Minoxidil also increased the secretion of growth factors from ASCs, including chemokine (C-X-C motif) ligand 1 (CXCL1), platelet-derived endothelial cell growth factor (PD-ECGF), and platelet-derived growth factor-C (PDGF-C). Minoxidil increased extracellular signal–regulated kinases 1/2 (ERK1/2) phosphorylation, and concomitant upregulation of PD-ECGF and PDGF-C mRNA levels were attenuated by an ERK inhibitor. Subcutaneous injection of CXCL1, PD-ECGF, or PDGF-C enhanced anagen induction in mice, and both CXCL1 and PDGF-C increased hair length in ex vivo organ culture. Treatment with CXCL1, PD-ECGF, or PDGF-C also increased the proliferation index in DP cells. Finally, topical application of CXCL1, PD-ECGF, or PDGF-C with 2% minoxidil enhanced anagen induction when compared to minoxidil alone. Minoxidil stimulates ASC motility and increases paracrine growth factor signaling. Minoxidil-stimulated secretion of growth factors by ASCs may enhance hair growth by promoting DP proliferation. Therefore, minoxidil can be used as an ASC preconditioning agent for hair regeneration.
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40
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Ginsenoside Rg1 and platelet-rich fibrin enhance human breast adipose-derived stem cell function for soft tissue regeneration. Oncotarget 2018; 7:35390-403. [PMID: 27191987 PMCID: PMC5085237 DOI: 10.18632/oncotarget.9360] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2015] [Accepted: 04/11/2016] [Indexed: 02/01/2023] Open
Abstract
Adipose-derived stem cells (ASCs) can be used to repair soft tissue defects, wounds, burns, and scars and to regenerate various damaged tissues. The cell differentiation capacity of ASCs is crucial for engineered adipose tissue regeneration in reconstructive and plastic surgery. We previously reported that ginsenoside Rg1 (G-Rg1 or Rg1) promotes proliferation and differentiation of ASCs in vitro and in vivio. Here we show that both G-Rg1 and platelet-rich fibrin (PRF) improve the proliferation, differentiation, and soft tissue regeneration capacity of human breast adipose-derived stem cells (HBASCs) on collagen type I sponge scaffolds in vitro and in vivo. Three months after transplantation, tissue wet weight, adipocyte number, intracellular lipid, microvessel density, and gene and protein expression of VEGF, HIF-1α, and PPARγ were higher in both G-Rg1- and PRF-treated HBASCs than in control grafts. More extensive new adipose tissue formation was evident after treatment with G-Rg1 or PRF. In summary, G-Rg1 and/or PRF co-administration improves the function of HBASCs for soft tissue regeneration engineering.
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Long L, Qiu H, Cai B, Chen N, Lu X, Zheng S, Ye X, Li Y. Hyperglycemia induced testicular damage in type 2 diabetes mellitus rats exhibiting microcirculation impairments associated with vascular endothelial growth factor decreased via PI3K/Akt pathway. Oncotarget 2018; 9:5321-5336. [PMID: 29435181 PMCID: PMC5797052 DOI: 10.18632/oncotarget.23915] [Citation(s) in RCA: 70] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Accepted: 12/01/2017] [Indexed: 12/13/2022] Open
Abstract
As an endocrine disease, type 2 diabetes mellitus (T2DM) can cause testicular damage which induces male infertility. However, the underlying mechanism is still not clear. We prove that T2DM induced testicular microcirculation impairment involves the decrease of VEGF and these actions are regulated by PI3K/Akt pathway. In our study, rats were divided into three groups (n=8): control group, diabetes group and diabetes + VEGF group. Intraperitoneal injection of streptozotocin (STZ, 65mg/Kg, at 9th week) and daily high-fat diet were used to establish T2DM rat model. Serum glucose in diabetes group and diabetes + VEGF group obviously exceeded 13mmol/L after STZ injection. Immunohistochemical studies indicated that VEGF level in diabetes group significantly decreased. In diabetes group, testicular blood velocity and vascular area reduced evaluated by Doppler and FITC. Furthermore, atrophic testicular morphology and increasing apoptosis cells were evaluated by haematoxylin and eosin staining and TUNEL assay. In diabetes + VEGF group, the administration of VEGF (intraperitoneally, 10mg/kg) can significantly alleviated hyperglycemia-induced impairment of testes in above aspects. Finally, we used Western blot to analyze the mechanism of hyperglycemia-induced testicular VEGF decrease. The results indicated that hyperglycemia-induced VEGF decreased is regulated by PI3K/Akt pathway in Rats testicular sertoli cells (RTSCs). Together, we demonstrate that T2DM can reduce testicular VEGF expression, which results in testicular microcirculation impairment, and then induces testicular morphological disarrangement and functional disorder. These actions are triggered by PI3K/Akt pathway. Our findings provide solid evidence for VEGF becoming a therapeutic target in T2DM related male infertility.
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Affiliation(s)
- Lingli Long
- Translation Medicine Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Han Qiu
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Bing Cai
- The Reproductive Center of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Ningning Chen
- Department of Orthopedics, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Xiaofang Lu
- Department of Pathology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Shuhui Zheng
- Translation Medicine Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Xiaoxin Ye
- University of New South Wales, Sydney, Australia
| | - Yubin Li
- The Reproductive Center of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
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Oliva-Olivera W, Coín-Aragüez L, Lhamyani S, Salas J, Gentile AM, Romero-Zerbo SY, Zayed H, Valderrama J, Tinahones FJ, El Bekay R. Differences in the neovascular potential of thymus versus subcutaneous adipose-derived stem cells from patients with myocardial ischaemia. J Tissue Eng Regen Med 2018; 12:e1772-e1784. [PMID: 29024495 DOI: 10.1002/term.2585] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 07/19/2017] [Accepted: 10/03/2017] [Indexed: 12/13/2022]
Abstract
Adipose tissue-derived multipotent mesenchymal cells (ASCs) participate in the information of blood vessels under hypoxic conditions. It is probable that the susceptibility of ASCs to the influence of age and ageing-associated pathologies compromises their therapeutic effectiveness depending on the adipose tissue depot. Our aim was to examine the neovascular potential under hypoxic conditions of ASCs-derived from thymic (thymASCs) and subcutaneous (subASCs) adipose tissue from 39 subjects with and without type 2 diabetes mellitus (T2DM) and of different ages who were undergoing coronary bypass surgery. We confirmed a significant decrease in the percentage of CD34+ CD31- CD45- subASCs in the cell yield of subASCs and in the survival of cultured endothelial cells in the medium conditioned by the hypox-subASCs with increasing patient age, which was not observed in thymASCs. Whereas the length of the tubules generated by hypox-subASCs tended to correlate negatively with patient age, tubule formation capacity of the hypoxic thymASCs increased significantly. Compared with subASCs, thymASCs from subjects over age 65 and without T2DM showed higher cell yield, tubule formation capacity, vascular endothelial growth factor secretion levels, and ability to promote endothelial cell survival in their conditioned medium. Deterioration in subASCs neovascular potential relative to thymASCs derived from these subjects was accompanied by higher expression levels of NOX4 mRNA and fibrotic proteins. Our results indicate that thymASCs from patients over age 65 and without T2DM have a higher angiogenic potential than those from the other patient groups, suggesting they may be a good candidate for angiogenic therapy in subjects undergoing coronary bypass surgery.
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Affiliation(s)
- Wilfredo Oliva-Olivera
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Clinical Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Malaga, Spain.,CIBER-The Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition, Institute of Health Carlos III, Malaga, Spain
| | - Leticia Coín-Aragüez
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Clinical Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Malaga, Spain.,CIBER-The Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition, Institute of Health Carlos III, Malaga, Spain
| | | | - Julián Salas
- Cardiovascular Surgery Department, Carlos Haya University Hospital, Malaga, Spain
| | | | - Silvana-Yanina Romero-Zerbo
- Unidad de Gestión Clínica Intercentros de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Malaga, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Malaga, Spain
| | - Hatem Zayed
- Biomedical Sciences Program, Health Sciences Department, College of Arts and Sciences, Qatar University, Doha, Qatar
| | - Jf Valderrama
- Cardiovascular Surgery Department, Carlos Haya University Hospital, Malaga, Spain
| | - Francisco José Tinahones
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Clinical Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Malaga, Spain.,CIBER-The Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition, Institute of Health Carlos III, Malaga, Spain
| | - Rajaa El Bekay
- CIBER-The Spanish Biomedical Research Centre in Physiopathology of Obesity and Nutrition, Institute of Health Carlos III, Malaga, Spain.,Unidad de Gestión Clínica Intercentros de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga/Universidad de Málaga, Malaga, Spain
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Sugg KB, Markworth JF, Disser NP, Rizzi AM, Talarek JR, Sarver DC, Brooks SV, Mendias CL. Postnatal tendon growth and remodeling require platelet-derived growth factor receptor signaling. Am J Physiol Cell Physiol 2017; 314:C389-C403. [PMID: 29341790 DOI: 10.1152/ajpcell.00258.2017] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Platelet-derived growth factor receptor (PDGFR) signaling plays an important role in the fundamental biological activities of many cells that compose musculoskeletal tissues. However, little is known about the role of PDGFR signaling during tendon growth and remodeling in adult animals. Using the hindlimb synergist ablation model of tendon growth, our objectives were to determine the role of PDGFR signaling in the adaptation of tendons subjected to a mechanical growth stimulus, as well as to investigate the biological mechanisms behind this response. We demonstrate that both PDGFRs, PDGFRα and PDGFRβ, are expressed in tendon fibroblasts and that the inhibition of PDGFR signaling suppresses the normal growth of tendon tissue in response to mechanical growth cues due to defects in fibroblast proliferation and migration. We also identify membrane type-1 matrix metalloproteinase (MT1-MMP) as an essential proteinase for the migration of tendon fibroblasts through their extracellular matrix. Furthermore, we report that MT1-MMP translation is regulated by phosphoinositide 3-kinase/Akt signaling, while ERK1/2 controls posttranslational trafficking of MT1-MMP to the plasma membrane of tendon fibroblasts. Taken together, these findings demonstrate that PDGFR signaling is necessary for postnatal tendon growth and remodeling and that MT1-MMP is a critical mediator of tendon fibroblast migration and a potential target for the treatment of tendon injuries and diseases.
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Affiliation(s)
- Kristoffer B Sugg
- Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, Michigan.,Department of Molecular and Integrative Physiology, University of Michigan Medical School , Ann Arbor, Michigan.,Department of Surgery, Section of Plastic and Reconstructive Surgery, University of Michigan Medical School, Ann Arbor, Michigan
| | - James F Markworth
- Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, Michigan
| | - Nathaniel P Disser
- Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, Michigan
| | - Andrew M Rizzi
- Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, Michigan
| | - Jeffrey R Talarek
- Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, Michigan.,Department of Molecular and Integrative Physiology, University of Michigan Medical School , Ann Arbor, Michigan
| | - Dylan C Sarver
- Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, Michigan
| | - Susan V Brooks
- Department of Molecular and Integrative Physiology, University of Michigan Medical School , Ann Arbor, Michigan.,Department of Biomedical Engineering, University of Michigan Medical School , Ann Arbor, Michigan
| | - Christopher L Mendias
- Department of Orthopaedic Surgery, University of Michigan Medical School , Ann Arbor, Michigan.,Department of Molecular and Integrative Physiology, University of Michigan Medical School , Ann Arbor, Michigan.,Hospital for Special Surgery , New York, New York
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Oliva-Olivera W, Moreno-Indias I, Coín-Aragüez L, Lhamyani S, Alcaide Torres J, Fernández-Veledo S, Vendrell J, Camargo A, El Bekay R, Tinahones FJ. Different response to hypoxia of adipose-derived multipotent cells from obese subjects with and without metabolic syndrome. PLoS One 2017; 12:e0188324. [PMID: 29166648 PMCID: PMC5699836 DOI: 10.1371/journal.pone.0188324] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 11/03/2017] [Indexed: 12/27/2022] Open
Abstract
Background/Objectives Multiple studies suggest that hypoxia, together with inflammation, could be one of the phenomena involved in the onset and progression of obesity-related insulin resistance. In addition, dysfunction of adipose tissue in obese subjects with metabolic syndrome is associated with decreased angiogenesis. However, some subjects with a high body mass index do not develop metabolic abnormalities associated with obesity. The aim of the current study was to examine the neovascular properties of visceral adipose tissue-derived multipotent mesenchymal cells subjected to hypoxia (hypox-visASCs) from normal-weight subjects (Nw) and obese patients with metabolic syndrome (MS) and without metabolic syndrome (NonMS). Methods This was a 2-year study to enroll subjects who underwent bariatric surgery or cholecystectomy. Eight patients who underwent either bariatric surgery or cholecystectomy (27 patients) participated in the study. Visceral adipose tissue samples from Nw, MS and NonMS subjects were processed by enzymatic digestion. VisASCs cultured under hypoxic conditions were characterized by tubule formation assay, ELISA, flow cytometry, migration rate, and qRT-PCR, and the effects of visASCs-conditioned medium on survival and endothelial cell tubule formation were evaluated. Results Hypox-visASCs from NonMS subjects showed a greater capacity for tubule formation than hypox-visASCs from Nw and MS subjects. The lower percentage of CD140b+/CD44+ and CD140b+/CD184+ cells observed in hypox-visASCs from NonMS subjects compared to MS subjects was accompanied not only by a lower migration rate from the chemotactic effects of stromal cell derived factor 1α, but also by lower levels of NOX5 mRNA expression. While the levels of monocyte chemoattractant protein 1 mRNA expressed by hypox-visASCs correlated positively with the body mass index and waist circumference of the subjects, the concentration of vascular endothelial growth factor present in hypox-visASC-conditioned culture medium decreased significantly with increasing plasma glucose. The survival rate and tubules formed by endothelial cells cultured in hypox-visASC-conditioned medium decreased significantly with increasing homeostasis model assessment to quantify insulin resistance. Conclusions Our results suggest that hypox-visASCs from NonMS subjects could promote healthy adipose tissue expansion, while hypox-visASCs from MS subjects appear to contribute to the decreased angiogenic potential and increased inflammation underlying adipose tissue dysfunction in obesity. Our results emphasize the importance of taking into account not only the BMI but also the metabolic profile of the subjects during the implementation of ASCs-based therapy to promote neovascularization.
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Affiliation(s)
- Wilfredo Oliva-Olivera
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Málaga, Spain
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
- * E-mail: (FJT); (REB); (WOO)
| | - Isabel Moreno-Indias
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Málaga, Spain
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Leticia Coín-Aragüez
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Málaga, Spain
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Said Lhamyani
- Research Laboratory, Science School, University of Málaga (UMA), Málaga, Spain
| | - Juan Alcaide Torres
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Málaga, Spain
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
| | - Sonia Fernández-Veledo
- Hospital Universitari de Tarragona Joan XXIII, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovirai Virgili, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Joan Vendrell
- Hospital Universitari de Tarragona Joan XXIII, Institut d'Investigació Sanitària Pere Virgili, Universitat Rovirai Virgili, Tarragona, Spain
- CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain
| | - Antonio Camargo
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
- Lipids and Atherosclerosis Unit, IMIBIC/Reina Sofia University Hospital/University of Córdoba, Córdoba, Spain
| | - Rajaa El Bekay
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Málaga, Spain
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
- * E-mail: (FJT); (REB); (WOO)
| | - Francisco José Tinahones
- Department of Clinical Endocrinology and Nutrition, Institute of Biomedical Research of Málaga (IBIMA), Hospital of Málaga (Virgen de la Victoria), University of Málaga (UMA), Málaga, Spain
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, Madrid, Spain
- * E-mail: (FJT); (REB); (WOO)
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Park SJ, Nhiem NX, Tai BH, Le Tuan Anh H, Oh SH, Sung JH, Kim N, Yoo G, Park JH, Kwak HJ, Loan PT, Kim SH, Van Kiem P. Proliferation Effects on Hair Growth of Compounds Isolated from the Bark of Dalbergia oliveri. Nat Prod Commun 2017. [DOI: 10.1177/1934578x1701201117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
One new isoflavane, 7,4′-dihydroxy-isoflavanquinone (1), together with ten known compounds (2–11) were isolated from the bark of Dalbergia oliveri Prain. The structures of compounds were determined on the basis of extensive spectroscopic methods, including 1D and 2D NMR and CD spectroscopic data. Using a cell proliferation assay, the isolated compounds were evaluated for their proliferation effects on hair growth. (3 R)-5’-Methoxyvestitol (2) and (6a R,11a R)-3,8-dihydroxy-9-methoxypterocarpan (10) significantly increased the proliferation of immortalized dermal papilla cells (iDPC).
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Affiliation(s)
- Seon Ju Park
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea
| | - Nguyen Xuan Nhiem
- Institute of Marine Biochemistry, Vietnam Academy of Science and Technology (VAST), Hanoi, Vietnam
| | - Bui Huu Tai
- Institute of Marine Biochemistry, Vietnam Academy of Science and Technology (VAST), Hanoi, Vietnam
| | - Hoang Le Tuan Anh
- Institute of Marine Biochemistry, Vietnam Academy of Science and Technology (VAST), Hanoi, Vietnam
| | - Seok Hyun Oh
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea
| | - Jong-Hyuk Sung
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea
- STEMORE Co. Ltd., Incheon, Republic of South Korea
| | - Nanyoung Kim
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea
| | - Guijae Yoo
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea
| | - Jun Hyung Park
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea
| | - Hee Jae Kwak
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea
| | | | - Seung Hyun Kim
- College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Korea
| | - Phan Van Kiem
- Institute of Marine Biochemistry, Vietnam Academy of Science and Technology (VAST), Hanoi, Vietnam
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46
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The Use of Adipose-Derived Stem Cells in Selected Skin Diseases (Vitiligo, Alopecia, and Nonhealing Wounds). Stem Cells Int 2017; 2017:4740709. [PMID: 28904532 PMCID: PMC5585652 DOI: 10.1155/2017/4740709] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2017] [Revised: 06/03/2017] [Accepted: 06/18/2017] [Indexed: 12/15/2022] Open
Abstract
The promising results derived from the use of adipose-derived stem cells (ADSCs) in many diseases are a subject of observation in preclinical studies. ADSCs seem to be the ideal cell population for the use in regenerative medicine due to their easy isolation, nonimmunogenic properties, multipotential nature, possibilities for differentiation into various cell lines, and potential for angiogenesis. This article reviews the current data on the use of ADSCs in the treatment of vitiligo, various types of hair loss, and the healing of chronic wounds.
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47
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Lim Y, Lee M, Jeong H, Kim H. Involvement of PI3K and MMP1 in PDGF-induced Migration of Human Adipose-derived Stem Cells. Dev Reprod 2017; 21:167-180. [PMID: 28785738 PMCID: PMC5532309 DOI: 10.12717/dr.2017.21.2.167] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 05/09/2017] [Accepted: 05/11/2017] [Indexed: 12/11/2022]
Abstract
Human adult stem cells have widely been examined for their clinical application including their wound healing effect in vivo. To function as therapeutic cells, however, cells must represent the ability of directed migration in response to signals. This study aimed to investigate the mechanism of platelet-derived growth factor (PDGF)-induced migration of the human abdominal adipose-derived stem cells (hADSCs) in vitro. A general matrix metalloproteinase (MMP) inhibitor or a MMP2 inhibitor significantly inhibited the PDGF-induced migration. PDGF treatment exhibited greater mRNA level and denser protein level of MMP1. The conditioned medium of PDGF-treated cells showed a caseinolytic activity of MMP1. Transfection of cells with siRNA against MMP1 significantly inhibited MMP1 expression, its caseinolytic activity, and cell migration following PDGF treatment. Phosphatidylinositol 3-kinase (PI3K) inhibitor reduced the migration by about 50% without affecting ERK and MLC proteins. Rho-associated protein kinase inhibitor mostly abolished the migration and MLC proteins. The results suggest that PDGF might signal hADSCs through PI3K, and MMP1 activity could play an important role in this PDGF-induced migration in vitro.
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Affiliation(s)
- Yoonhwa Lim
- Dept. of Biotechnology, Seoul Women's University, Seoul 01797, Korea
| | - Minji Lee
- Dept. of Biotechnology, Seoul Women's University, Seoul 01797, Korea
| | - Hyeju Jeong
- Dept. of Biotechnology, Seoul Women's University, Seoul 01797, Korea
| | - Haekwon Kim
- Dept. of Biotechnology, Seoul Women's University, Seoul 01797, Korea
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Diao S, Lin X, Wang L, Dong R, Du J, Yang D, Fan Z. Analysis of gene expression profiles between apical papilla tissues, stem cells from apical papilla and cell sheet to identify the key modulators in MSCs niche. Cell Prolif 2017; 50. [DOI: 18.doi: 10.1111/cpr.12337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/19/2025] Open
Abstract
AbstractObjectivesThe microenvironmental niche plays the key role for maintaining the cell functions. The stem cells from apical papilla (SCAPs) are important for tooth development and regeneration. However, there is limited knowledge about the key factors in niche for maintaining the function of SCAPs. In this study, we analyse the gene expression profiles between apical papilla tissues, SCAPs and SCAPs cell sheet to identify the key genes in SCAPs niche.Materials and methodsMicroarray assays and bioinformatic analysis were performed to screen the differential genes between apical papilla tissues and SCAPs, and SCAPs and SCAPs cell sheet. Recombinant human BMP6 protein was used in SCAPs. Then CCK‐8 assay, CFSE assay, alkaline phosphatase activity, alizarin red staining, quantitative calcium analysis and real‐time reverse transcriptase‐polymerase chain reaction were performed to investigate the cell proliferation and differentiation potentials of SCAPs.ResultsMicroarray analysis found that 846 genes were up‐regulated and 1203 genes were down‐regulated in SCAPs compared with apical papilla tissues. While 240 genes were up‐regulated and 50 genes were down‐regulated in SCAPs compared to in SCAPs cell sheet. Moreover, only 31 gene expressions in apical papilla tissues were recovered in cell sheet compared with SCAPs. Bioinformatic analysis identified that TGF‐β, WNT and MAPK signalling pathways may play an important role in SCAPs niche. Based on the analysis, we identified one key growth factor in niche, BMP6, which could enhance the cell proliferation, the osteo/dentinogenic, neurogenic and angiogenic differentiation potentials of SCAPs.ConclusionsOur results provided insight into the mechanisms of the microenvironmental niche which regulate the function of SCAPs, and identified the key candidate genes in niche to promote mesenchymal stem cells‐mediated dental tissue regeneration.
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Affiliation(s)
- Shu Diao
- Laboratory of Molecular Signaling and Stem Cells Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing China
- Department of Pediatric dentistry Capital Medical University School of Stomatology Beijing China
| | - Xiao Lin
- Laboratory of Molecular Signaling and Stem Cells Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing China
- Department of Implant Dentistry Capital Medical University School of Stomatology Beijing China
| | - Liping Wang
- Laboratory of Molecular Signaling and Stem Cells Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing China
| | - Rui Dong
- Laboratory of Molecular Signaling and Stem Cells Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing China
| | - Juan Du
- Laboratory of Molecular Signaling and Stem Cells Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing China
- Molecular Laboratory for Gene Therapy and Tooth Regeneration Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing China
| | - Dongmei Yang
- Laboratory of Molecular Signaling and Stem Cells Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing China
- Department of Pediatric dentistry Capital Medical University School of Stomatology Beijing China
| | - Zhipeng Fan
- Laboratory of Molecular Signaling and Stem Cells Therapy Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction Capital Medical University School of Stomatology Beijing China
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Diao S, Lin X, Wang L, Dong R, Du J, Yang D, Fan Z. Analysis of gene expression profiles between apical papilla tissues, stem cells from apical papilla and cell sheet to identify the key modulators in MSCs niche. Cell Prolif 2017; 50. [PMID: 28145066 DOI: 10.1111/cpr.12337] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 01/04/2017] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVES The microenvironmental niche plays the key role for maintaining the cell functions. The stem cells from apical papilla (SCAPs) are important for tooth development and regeneration. However, there is limited knowledge about the key factors in niche for maintaining the function of SCAPs. In this study, we analyse the gene expression profiles between apical papilla tissues, SCAPs and SCAPs cell sheet to identify the key genes in SCAPs niche. MATERIALS AND METHODS Microarray assays and bioinformatic analysis were performed to screen the differential genes between apical papilla tissues and SCAPs, and SCAPs and SCAPs cell sheet. Recombinant human BMP6 protein was used in SCAPs. Then CCK-8 assay, CFSE assay, alkaline phosphatase activity, alizarin red staining, quantitative calcium analysis and real-time reverse transcriptase-polymerase chain reaction were performed to investigate the cell proliferation and differentiation potentials of SCAPs. RESULTS Microarray analysis found that 846 genes were up-regulated and 1203 genes were down-regulated in SCAPs compared with apical papilla tissues. While 240 genes were up-regulated and 50 genes were down-regulated in SCAPs compared to in SCAPs cell sheet. Moreover, only 31 gene expressions in apical papilla tissues were recovered in cell sheet compared with SCAPs. Bioinformatic analysis identified that TGF-β, WNT and MAPK signalling pathways may play an important role in SCAPs niche. Based on the analysis, we identified one key growth factor in niche, BMP6, which could enhance the cell proliferation, the osteo/dentinogenic, neurogenic and angiogenic differentiation potentials of SCAPs. CONCLUSIONS Our results provided insight into the mechanisms of the microenvironmental niche which regulate the function of SCAPs, and identified the key candidate genes in niche to promote mesenchymal stem cells-mediated dental tissue regeneration.
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Affiliation(s)
- Shu Diao
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.,Department of Pediatric dentistry, Capital Medical University School of Stomatology, Beijing, China
| | - Xiao Lin
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.,Department of Implant Dentistry, Capital Medical University School of Stomatology, Beijing, China
| | - Liping Wang
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
| | - Rui Dong
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
| | - Juan Du
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.,Molecular Laboratory for Gene Therapy and Tooth Regeneration, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
| | - Dongmei Yang
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China.,Department of Pediatric dentistry, Capital Medical University School of Stomatology, Beijing, China
| | - Zhipeng Fan
- Laboratory of Molecular Signaling and Stem Cells Therapy, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Capital Medical University School of Stomatology, Beijing, China
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Bethke E, Pinchuk B, Renn C, Witt L, Schlosser J, Peifer C. From Type I to Type II: Design, Synthesis, and Characterization of Potent Pyrazin-2-ones as DFG-Out Inhibitors of PDGFRβ. ChemMedChem 2016; 11:2664-2674. [PMID: 27885822 DOI: 10.1002/cmdc.201600494] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 10/30/2016] [Indexed: 11/09/2022]
Abstract
Reversible protein kinase inhibitors that bind in the ATP cleft can be classified as type I or type II binders. Of these, type I inhibitors address the active form, whereas type II inhibitors typically lock the kinase in an inactive form. At the molecular level, the conformation of the flexible activation loop holding the key DFG motif controls access to the ATP site, thereby determining an active or inactive kinase state. Accordingly, type I and type II kinase inhibitors bind to so-called DFG-in or DFG-out conformations, respectively. Based on our former study on highly selective platelet-derived growth factor receptor β (PDGFRβ) pyrazin-2-one type I inhibitors, we expanded this scaffold toward the deep pocket, yielding the highly potent and effective type II inhibitor 5 (4-[(4-methylpiperazin-1-yl)methyl]-N-[3-[[6-oxo-5-(3,4,5-trimethoxyphenyl)-1H-pyrazin-3-yl]methyl]phenyl]benzamide). In vitro characterization, including selectivity panel data from activity-based assays (300 kinases) and affinity-based assays (97 kinases) of these PDGFRβ type I (1; 5-(4-hydroxy-3-methoxy-phenyl)-3-(3,4,5-trimethoxyphenyl)-1H-pyrazin-2-one) and II (5) inhibitors showing the same pyrazin-2-one chemotype are compared. Implications are discussed regarding the data for selectivity and efficacy of type I and type II ligands.
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Affiliation(s)
- Eugen Bethke
- Christian Albrechts University of Kiel, Institute of Pharmacy, Gutenbergstr. 76, 24118, Kiel, Germany
| | - Boris Pinchuk
- Christian Albrechts University of Kiel, Institute of Pharmacy, Gutenbergstr. 76, 24118, Kiel, Germany
| | - Christian Renn
- Christian Albrechts University of Kiel, Institute of Pharmacy, Gutenbergstr. 76, 24118, Kiel, Germany
| | - Lydia Witt
- Christian Albrechts University of Kiel, Institute of Pharmacy, Gutenbergstr. 76, 24118, Kiel, Germany
| | - Joachim Schlosser
- Christian Albrechts University of Kiel, Institute of Pharmacy, Gutenbergstr. 76, 24118, Kiel, Germany
| | - Christian Peifer
- Christian Albrechts University of Kiel, Institute of Pharmacy, Gutenbergstr. 76, 24118, Kiel, Germany
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