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Qin W, Nie X, Su H, Ding Y, He L, Liu K, Hou J, Pan K, He L, Yang S, Li L, Yang S, Peng X, Zhao J, Guan J, Kuang X, Hua Q. Efficacy and safety of unilateral tibial cortex transverse transport on bilateral diabetic foot ulcers: A propensity score matching study. J Orthop Translat 2023; 42:137-146. [PMID: 37736148 PMCID: PMC10509564 DOI: 10.1016/j.jot.2023.08.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 07/12/2023] [Accepted: 08/02/2023] [Indexed: 09/23/2023] Open
Abstract
BACKGROUND Tibial Cortex Transverse Transport (TTT) has been demonstrated to be an effective treatment for unilateral diabetic foot ulcers (UDFUs). However, this retrospective study was designed to compare the efficacy and safety of unilateral TTT on bilateral diabetic foot ulcers (BDFUs). METHODS This retrospective study included a review of patients with TTT treated from January 2017 to August 2019, Propensity Score Matching (PSM) was performed to compare patients with BDFUs to those with UDFUs. Ulcer healing, recurrence, and major amputation rates were evaluated at 1-year follow-up. Changes in foot vessels were assessed in the BDFUs group using computed tomography angiography (CTA). RESULTS A total of 140 patients with DFUs (106 UDFUs and 34 BDFUs) were included in the study. UDFUs and BDFUs were matched in a 1:1 ratio (34 in each group) using PSM. No significant difference was observed at 1-year-follow-up [91.2% (31/34) vs. 76.5% (26/34), OR 0.315 (95% CI 0.08 to 1.31), P = 0.10] and 6-month-follow-up [70.6% (24/34) vs. 50.0% (17/34), OR 0.85 (95% CI 0.15 to 1.13), P = 0.08] in two groups. Significant differences in rates of major amputation and recurrence between the groups (P > 0.05) were not observed. The BDFUs group appeared more angiogenesis of the foot by CTA after 8 weeks of operation. CONCLUSION Results of this study suggest that severe BDFUs can be effectively treated by unilateral TTT. TTT is easy to operate and effective, which may be a good alternative for treating severe BDFUs. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE In previous retrospective clinical studies, TTT has demonstrated promising clinical outcomes in the management of diabetic foot ulcers. In this current study, we aim to investigate the potential use of TTT in treating distant tissue defects by evaluating the limited availability and safety of TTT for the management of bilateral diabetic foot. While additional basic and clinical research is necessary to fully elucidate the underlying mechanisms, our study offers insight into the potential therapeutic use of TTT for this condition.
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Affiliation(s)
- Wencong Qin
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Xinyu Nie
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Research Centre for Regenerative Medicine, Guangxi Medical University, China
- Department of Orthopedics, The Second Hospital, Jilin University, Changchun, Jilin, 130042, China
| | - Hongjie Su
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical Bio-Resource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Research Centre for Regenerative Medicine, Guangxi Medical University, China
| | - Yi Ding
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Lihuan He
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Department of Orthopedics, Sinopharm Dongfeng General Hospital of Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Kaibing Liu
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Jun Hou
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical Bio-Resource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Research Centre for Regenerative Medicine, Guangxi Medical University, China
| | - Kaixiang Pan
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Yulin Campus of Guangxi Medical University, Yulin, Guangxi, 537406, China
| | - Liexun He
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Sijie Yang
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical Bio-Resource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Research Centre for Regenerative Medicine, Guangxi Medical University, China
| | - Lisha Li
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Shenghui Yang
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical Bio-Resource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Research Centre for Regenerative Medicine, Guangxi Medical University, China
| | - Xiao Peng
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
| | - Jinming Zhao
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical Bio-Resource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Research Centre for Regenerative Medicine, Guangxi Medical University, China
| | - Jack Guan
- Bay Area Foot and Ankle Medical Clinic, San Jose, 3150, California, USA
| | - Xiaocong Kuang
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Yulin Campus of Guangxi Medical University, Yulin, Guangxi, 537406, China
- Research Centre for Regenerative Medicine, Guangxi Medical University, China
| | - Qikai Hua
- Department of Bone and Joint Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China
- Guangxi Diabetic Foot Salvage Engineering Research Center, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Collaborative Innovation Centre of Regenerative Medicine and Medical Bio-Resource Development and Application Co-constructed by the Province and Ministry, Guangxi Medical University, Nanning, Guangxi, 530021, China
- Research Centre for Regenerative Medicine, Guangxi Medical University, China
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Han Z, He X, Feng Y, Jiang W, Zhou N, Huang X. Hsp20 Promotes Endothelial Progenitor Cell Angiogenesis via Activation of PI3K/Akt Signaling Pathway under Hypoxia. Tissue Eng Regen Med 2022; 19:1251-1266. [PMID: 36042130 PMCID: PMC9679071 DOI: 10.1007/s13770-022-00481-1] [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: 03/10/2022] [Revised: 07/09/2022] [Accepted: 07/13/2022] [Indexed: 10/14/2022] Open
Abstract
BACKGROUND Mandibular distraction osteogenesis (MDO) is a kind of endogenous tissue engineering technology that lengthens the jaw and opens airway so that a patient can breathe safely and comfortably on his or her own. Endothelial progenitor cells (EPCs) are crucial for MDO-related angiogenesis. Moreover, emerging evidence suggests that heat shock protein 20 (Hsp20) modulates angiogenesis under hypoxic conditions. However, the specific role of Hsp20 in EPCs, in the context of MDO, is not yet known. The aim of this study was to explore the expression of Hsp20 during MDO and the effects of Hsp20 on EPCs under hypoxia. METHODS Mandibular distraction osteogenesis and mandibular bone defect (MBD) canine model were established. The expression of CD34, CD133, HIF-1α, and Hsp20 in callus was detected by immunofluorescence on day 14 after surgery. Canine bone marrow EPCs were cultured, with or without optimal cobalt chloride (CoCl2) concentration. Hypoxic effects, caused by CoCl2, were evaluated by means of the cell cycle, cell apoptosis, transwell cell migration, and tube formation assays. The Hsp20/KDR/PI3K/Akt expression levels were evaluated via immunofluorescence, RT-qPCR, and western blot. Next, EPCs were incorporated with either Hsp20-overexpression or Hsp20-siRNA lentivirus. The resulting effects were evaluated as described above. RESULTS CD34, CD133, HIF-1α, and Hsp20 were displayed more positive in the callus of MDO compared with MBD. In addition, hypoxic conditions, generated by 0.1 mM CoCl2, in canine EPCs, accelerated cell proliferation, migration, tube formation, and Hsp20 expression. Hsp20 overexpression in EPCs significantly stimulated cell proliferation, migration, and tube formation, whereas Hsp20 inhibition produced the opposite effect. Additionally, the molecular mechanism was partly dependent on the KDR/PI3K/Akt pathway. CONCLUSION In summary, herein, we present a novel mechanism of Hsp20-mediated regulation of canine EPCs via Akt activation in a hypoxic microenvironment.
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Affiliation(s)
- Zhiqi Han
- Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, Guangxi, 530021, People's Republic of China
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, Guangxi, 530021, People's Republic of China
| | - Xuan He
- Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, Guangxi, 530021, People's Republic of China
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, Guangxi, 530021, People's Republic of China
| | - Yuan Feng
- Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, Guangxi, 530021, People's Republic of China
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, Guangxi, 530021, People's Republic of China
| | - Weidong Jiang
- Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, Guangxi, 530021, People's Republic of China
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, Guangxi, 530021, People's Republic of China
| | - Nuo Zhou
- Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China.
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China.
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, Guangxi, 530021, People's Republic of China.
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, Guangxi, 530021, People's Republic of China.
| | - Xuanping Huang
- Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China.
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, Guangxi, 530021, People's Republic of China.
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, Guangxi, 530021, People's Republic of China.
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, Guangxi, 530021, People's Republic of China.
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Liao F, Liao Z, Zhang T, Jiang W, Zhu P, Zhao Z, Shi H, Zhao D, Zhou N, Huang X. ECFC-derived exosomal THBS1 mediates angiogenesis and osteogenesis in distraction osteogenesis via the PI3K/AKT/ERK pathway. J Orthop Translat 2022; 37:12-22. [PMID: 36196150 PMCID: PMC9513111 DOI: 10.1016/j.jot.2022.08.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 07/24/2022] [Accepted: 08/09/2022] [Indexed: 11/30/2022] Open
Abstract
Background Distraction osteogenesis (DO) is a widely used bone regenerative technique. However, the DO process is slow, and the consolidation phase is long. Therefore, it is of great clinical significance to explore the mechanism of DO, and shorten its duration. Recent studies reported that stem cell exosomes may play an important role in promoting angiogenesis related to DO, but the mechanism remains unclear. Methods Canine endothelial colony-forming cells (ECFCs) were isolated and cultured, and the expression of THBS1 in canine ECFCs were inhibited using a lentiviral vector. The exosomes secreted by canine ECFCs were isolated and extracted, and the effect of exosomes on the angiogenic activity of Human umbilical vein endothelial cells (HUVECs) was detected by proliferation, migration, and tube formation experiments. WB and qRT-PCR were used to explore the effects and mechanisms of THBS1-mediated ECFC-Exos on HUVECs angiogenesis. Then, a mandibular distraction osteogenesis (MDO) model was established in adult male beagles, and exosomes were injected into the canine peripheral blood. Micro-CT, H&E, Masson, and IHC staining were used to explore the effects and mechanisms of THBS1-mediated ECFC-Exos on angiogenesis and osteogenesis in the DO area. Results ECFC-Exo accelerated HUVECs proliferation, migration and tube formation, and this ability was enhanced by inhibiting the expression of THBS1 in ECFC-Exo. Using Western blot-mediated detection, we demonstrated that inhibiting THBS1 expression in ECFCs-Exo activated PI3K, AKT, and ERK phosphorylation levels in HUVECs, which promoted VEGF and bFGF expressions. In the DO model of the canine mandible, ECFCs-Exo injected into the peripheral blood aggregated into the DO gap, thus promoting angiogenesis and bone formation in the DO tissue by reducing THBS1 expression in ECFC-Exo. Conclusion Our findings suggested that ECFC-Exos markedly enhances angiogenesis of endothelial cells, and promotes bone healing in canine MDO. Thus, THBS1 plays a crucial role in the ECFC-Exos-mediated regulation of canine MDO angiogenesis and bone remodeling. The translational potential of this article This study reveals that the angiogenic promotion via THBS1 suppression in ECFC-Exos may be a promising strategy for shortening the DO duration.
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Affiliation(s)
- Fengchun Liao
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, 10 Shuangyong Road, Nanning, 530021, People's Republic of China
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, 530021, People's Republic of China
| | - Ziqi Liao
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, 10 Shuangyong Road, Nanning, 530021, People's Republic of China
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, 530021, People's Republic of China
| | - Tao Zhang
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, 10 Shuangyong Road, Nanning, 530021, People's Republic of China
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, 530021, People's Republic of China
| | - Weidong Jiang
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, 10 Shuangyong Road, Nanning, 530021, People's Republic of China
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, 530021, People's Republic of China
| | - Peiqi Zhu
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, 10 Shuangyong Road, Nanning, 530021, People's Republic of China
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, 530021, People's Republic of China
| | - Zhenchen Zhao
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, 10 Shuangyong Road, Nanning, 530021, People's Republic of China
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, 530021, People's Republic of China
| | - Henglei Shi
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, 10 Shuangyong Road, Nanning, 530021, People's Republic of China
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, 530021, People's Republic of China
| | - Dan Zhao
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, 10 Shuangyong Road, Nanning, 530021, People's Republic of China
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, 530021, People's Republic of China
| | - Nuo Zhou
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, 10 Shuangyong Road, Nanning, 530021, People's Republic of China
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, 530021, People's Republic of China
- Corresponding author. Department of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, 10 Shuangyong Road, Nanning, 530021, People's Republic of China.
| | - Xuanping Huang
- Department of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, 10 Shuangyong Road, Nanning, 530021, People's Republic of China
- Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Nanning, 530021, People's Republic of China
- Corresponding author. Department of Oral and Maxillofacial Surgery, College of Stomatology, Guangxi Medical University, 10 Shuangyong Road, Nanning, 530021, People's Republic of China.
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Shi H, Zhao Z, Jiang W, Zhu P, Zhou N, Huang X. A Review Into the Insights of the Role of Endothelial Progenitor Cells on Bone Biology. Front Cell Dev Biol 2022; 10:878697. [PMID: 35686054 PMCID: PMC9173585 DOI: 10.3389/fcell.2022.878697] [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: 02/18/2022] [Accepted: 04/11/2022] [Indexed: 11/23/2022] Open
Abstract
In addition to its important transport functions, the skeletal system is involved in complex biological activities for the regulation of blood vessels. Endothelial progenitor cells (EPCs), as stem cells of endothelial cells (ECs), possess an effective proliferative capacity and a powerful angiogenic capacity prior to their differentiation. They demonstrate synergistic effects to promote bone regeneration and vascularization more effectively by co-culturing with multiple cells. EPCs demonstrate a significant therapeutic potential for the treatment of various bone diseases by secreting a combination of growth factors, regulating cellular functions, and promoting bone regeneration. In this review, we retrospect the definition and properties of EPCs, their interaction with mesenchymal stem cells, ECs, smooth muscle cells, and immune cells in bone regeneration, vascularization, and immunity, summarizing their mechanism of action and contribution to bone biology. Additionally, we generalized their role and potential mechanisms in the treatment of various bone diseases, possibly indicating their clinical application.
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Affiliation(s)
- Henglei Shi
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Disease Treatment, Guangxi Clinical Research Center for Craniofacia Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surg Deformity, Nanning, China
| | - Zhenchen Zhao
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Disease Treatment, Guangxi Clinical Research Center for Craniofacia Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surg Deformity, Nanning, China
| | - Weidong Jiang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Disease Treatment, Guangxi Clinical Research Center for Craniofacia Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surg Deformity, Nanning, China
| | - Peiqi Zhu
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Disease Treatment, Guangxi Clinical Research Center for Craniofacia Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surg Deformity, Nanning, China
| | - Nuo Zhou
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Disease Treatment, Guangxi Clinical Research Center for Craniofacia Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surg Deformity, Nanning, China
| | - Xuanping Huang
- Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Disease Treatment, Guangxi Clinical Research Center for Craniofacia Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surg Deformity, Nanning, China
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Liu X, Sun Y, Shen J, Min HS, Xu J, Chai Y. Strontium doped mesoporous silica nanoparticles accelerate osteogenesis and angiogenesis in distraction osteogenesis by activation of Wnt pathway. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2022; 41:102496. [PMID: 34838995 DOI: 10.1016/j.nano.2021.102496] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 10/11/2021] [Accepted: 10/26/2021] [Indexed: 12/27/2022]
Abstract
Distraction osteogenesis (DO) is a powerful method to reconstruct segmented bone defects in the extremities. However, the main shortcoming of DO is the time-consuming consolidation period. To shorten the consolidation process, two biocompatible inorganic ions, strontium and silicone, were applied to design a biocompatible material to enhance bone mineralization ability during DO. In the present study, we integrated strontium into a one-pot synthesis of mesoporous silica nanoparticles to obtain strontium-doped mesoporous silica nanoparticles characterized by a homogeneous spherical morphology and uniform ion-releasing dynamics. This dual-ion releasing osteogenic and angiogenic drug delivery system was investigated to accelerate mineralization in DO. Osteogenesis was promoted by activation of the Wnt/β-catenin pathway, while bone resorption was inhibited by reduction of the osteoclastogenic factor RANKL/OPG. In addition, angiogenesis may have been enhanced indirectly by secretion of vascular endothelial growth factor (VEGF) from bone marrow stem cells. Therefore, strontium-doped mesoporous silica nanoparticles could be a potential biomaterial candidate for accelerating consolidation during DO.
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Affiliation(s)
- Xuanzhe Liu
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yi Sun
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Junjie Shen
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Hong Sung Min
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Jia Xu
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
| | - Yimin Chai
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
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Yang S, Wang N, Ma Y, Guo S, Guo S, Sun H. Immunomodulatory effects and mechanisms of distraction osteogenesis. Int J Oral Sci 2022; 14:4. [PMID: 35067679 PMCID: PMC8784536 DOI: 10.1038/s41368-021-00156-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 12/20/2021] [Accepted: 12/29/2021] [Indexed: 11/11/2022] Open
Abstract
Distraction osteogenesis (DO) is widely used for bone tissue engineering technology. Immune regulations play important roles in the process of DO like other bone regeneration mechanisms. Compared with others, the immune regulation processes of DO have their distinct features. In this review, we summarized the immune-related events including changes in and effects of immune cells, immune-related cytokines, and signaling pathways at different periods in the process of DO. We aim to elucidated our understanding and unknowns about the immunomodulatory role of DO. The goal of this is to use the known knowledge to further modify existing methods of DO, and to develop novel DO strategies in our unknown areas through more detailed studies of the work we have done.
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Li Y, Yang Y, Wang M, Zhang X, Bai S, Lu X, Li Y, Waldorff EI, Zhang N, Lee WYW, Li G. High slew rate pulsed electromagnetic field enhances bone consolidation and shortens daily treatment duration in distraction osteogenesis. Bone Joint Res 2021; 10:767-779. [PMID: 34872332 PMCID: PMC8696558 DOI: 10.1302/2046-3758.1012.bjr-2021-0274.r1] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Aims Distraction osteogenesis (DO) is a useful orthopaedic procedure employed to lengthen and reshape bones by stimulating bone formation through controlled slow stretching force. Despite its promising applications, difficulties are still encountered. Our previous study demonstrated that pulsed electromagnetic field (PEMF) treatment significantly enhances bone mineralization and neovascularization, suggesting its potential application. The current study compared a new, high slew rate (HSR) PEMF signal, with different treatment durations, with the standard Food and Drug Administration (FDA)-approved signal, to determine if HSR PEMF is a better alternative for bone formation augmentation. Methods The effects of a HSR PEMF signal with three daily treatment durations (0.5, one, and three hours/day) were investigated in an established rat DO model with comparison of an FDA-approved classic signal (three hrs/day). PEMF treatments were applied to the rats daily for 35 days, starting from the distraction phase until termination. Radiography, micro-CT (μCT), biomechanical tests, and histological examinations were employed to evaluate the quality of bone formation. Results All rats tolerated the treatment well and no obvious adverse effects were found. By comparison, the HSR signal (three hrs/day) treatment group achieved the best healing outcome, in that endochondral ossification and bone consolidation were enhanced. In addition, HSR signal treatment (one one hr/day) had similar effects to treatment using the classic signal (three three hrs/day), indicating that treatment duration could be significantly shortened with the HSR signal. Conclusion HSR signal may significantly enhance bone formation and shorten daily treatment duration in DO, making it a potential candidate for a new clinical protocol for patients undergoing DO treatments. Cite this article: Bone Joint Res 2021;10(12):767–779.
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Affiliation(s)
- Yucong Li
- Department of Orthopaedic and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Yongkang Yang
- Department of Orthopaedic and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Ming Wang
- Department of Orthopaedic and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Xiaoting Zhang
- Department of Orthopaedic and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Shanshan Bai
- Department of Orthopaedic and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Xuan Lu
- Department of Orthopaedic and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Yuan Li
- Department of Orthopaedic and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Erik I Waldorff
- Research & Clinical Affairs, Orthofix Medical Inc, Lewisville, Texas, USA
| | - Nianli Zhang
- Research & Clinical Affairs, Orthofix Medical Inc, Lewisville, Texas, USA
| | - Wayne Yuk-Wai Lee
- Department of Orthopaedic and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,SH Ho Scoliosis Research Laboratory, Joint Scoliosis Research Center of the Chinese University of Hong Kong and Nanjing University, Department of Orthopaedics and Traumatology, The Chinese University of Hong Kong, Hong Kong, China.,Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Gang Li
- Department of Orthopaedic and Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China.,Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
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8
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Fang J, Xu J, Zhang Y, Chen H, Ma Z, Huang Z, Hu J. Stromal cell-derived factor-1 may play pivotal role in distraction-stimulated neovascularization of diabetic foot ulcer. Med Hypotheses 2021; 149:110548. [PMID: 33690002 DOI: 10.1016/j.mehy.2021.110548] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/16/2021] [Accepted: 02/24/2021] [Indexed: 02/05/2023]
Abstract
Diabetic foot ulcer (DFU) has become a major medical, social and economic concern worldwide. It is highly desirable to develop promising new solutions to effectively and appropriately treat DFU. In recent years, investigators have used an innovative technology called proximal tibial cortex transverse distraction (PTCTD) to treat DFU and have achieved satisfactory results in terms of improved wound healing and circumvention of amputation as a consequence of enhanced neovascularization and perfusion of the ulcerated feet after the operation, but the underlying mechanism has not been explored. Previous studies have suggested that in addition to stimulating osteogenesis, bone distraction also facilitates neovascularization, which may be associated with the chemokine stromal cell-derived factor-1 (SDF-1). As an important member of the chemokine family, SDF-1 is primarily responsible for the homing and migration of endothelial progenitor cells (EPCs) or bone marrow-derived mesenchymal stem cells (BMSCs), and plays a central role in the process of neovascularization. In vivo or in vitro experiments show that bone distraction can induce the expression of SDF-1 and increase its plasma concentration. Moreover, some researchers have found that an insufficient level of SDF-1 in the circulation and wounds of patients with DFU can lead to impaired neovascularization. Therefore, we believe that SDF-1 plays an important role in promoting neovascularization of DFU as a result of bone distraction. We summarize the currently relevant literature to put forward an undisclosed but meaningful mechanism of bone distraction in the treatment of DFU.
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Affiliation(s)
- Jiezhuang Fang
- Department of Orthopedics, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Jiankun Xu
- Department of Orthopedics, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Yuantao Zhang
- Department of Orthopedics, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Hongjiang Chen
- Department of Orthopedics, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Zebin Ma
- Department of Orthopedics, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Zhonglian Huang
- Department of Orthopedics, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China
| | - Jun Hu
- Department of Orthopedics, the First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
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9
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Zhu P, Jiang W, He S, Zhang T, Liao F, Liu D, An X, Huang X, Zhou N. Panax notoginseng saponins promote endothelial progenitor cell angiogenesis via the Wnt/β-catenin pathway. BMC Complement Med Ther 2021; 21:53. [PMID: 33557814 PMCID: PMC7869233 DOI: 10.1186/s12906-021-03219-z] [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: 11/16/2020] [Accepted: 01/14/2021] [Indexed: 12/29/2022] Open
Abstract
Background Distraction osteogenesis (DO) is an effective treatment in craniomaxillofacial surgery. However, the issue of sufficient blood supply at the regeneration tissue has limited its wide application. Panax notoginseng saponins (PNS) is a Traditional Chinese Medicine that is commonly used to treat a range of angiogenic diseases. However, the mechanisms whereby PNS alters angiogenesis in endothelial progenitor cells (EPCs) have yet to be clarified. Methods EPCs were identified by immunofluorescence, confirmed by their uptake of fluorescently labeled Dil-ac-LDL and FITC-UEA-1. EPCs were treated with different concentrations of PNS, and the effects of PNS on cell proliferation were measured on the optimal concentration of PNS determined. The effects of PNS on angiogenesis and migration, angiogenic cytokines mRNA expression and the proteins of the Wnt pathway were investigated. Then knocked down β-catenin in EPCs and treated with the optimum concentrational PNS, their angiogenic potential was evaluated in tube formation and migration assays. In addition, the expression of cytokines associated with angiogenesis and Wnt/β-catenin was then assessed via WB and RT-qPCR. Results We were able to determine the optimal concentration of PNS in the promotion of cell proliferation, tube formation, and migration to be 6.25 mg/L. PNS treatment increased the mRNA levels of VEGF, bFGF, VE-Cadherin, WNT3a, LRP5, β-catenin, and TCF4. After knocked down β-catenin expression, we found that PNS could sufficient to partially reverse the suppression of EPC angiogenesis. Conclusions Overall, 6.25 mg/L PNS can promote EPC angiogenesis via Wnt/β-catenin signaling pathway activation.
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Affiliation(s)
- Peiqi Zhu
- Guangxi Medical University, Nanning, 530021, People's Republic of China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction; Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
| | - Weidong Jiang
- Guangxi Medical University, Nanning, 530021, People's Republic of China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction; Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
| | - Shixi He
- Guangxi Medical University, Nanning, 530021, People's Republic of China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Tao Zhang
- Guangxi Medical University, Nanning, 530021, People's Republic of China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction; Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
| | - Fengchun Liao
- Guangxi Medical University, Nanning, 530021, People's Republic of China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction; Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
| | - Di Liu
- Guangxi Medical University, Nanning, 530021, People's Republic of China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Xiaoning An
- Guangxi Medical University, Nanning, 530021, People's Republic of China
| | - Xuanping Huang
- Guangxi Medical University, Nanning, 530021, People's Republic of China. .,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China. .,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction; Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China.
| | - Nuo Zhou
- Guangxi Medical University, Nanning, 530021, People's Republic of China. .,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China. .,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction; Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China.
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10
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Jiang W, Zhu P, Zhang T, Liao F, Yu Y, Liu Y, Shen H, Zhao Z, Huang X, Zhou N. MicroRNA-205 mediates endothelial progenitor functions in distraction osteogenesis by targeting the transcription regulator NOTCH2. Stem Cell Res Ther 2021; 12:101. [PMID: 33536058 PMCID: PMC7860583 DOI: 10.1186/s13287-021-02150-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Accepted: 01/07/2021] [Indexed: 12/24/2022] Open
Abstract
Background Distraction osteogenesis (DO) is a highly efficacious form of reconstructive bone regeneration, but its clinical utility is limited by the prolonged period required for bone consolidation to occur. Understanding the mechanistic basis for DO and shortening this consolidation phase thus represent promising approaches to improving the clinical utility of this procedure. Methods A mandibular DO (MDO) canine model was established, after which small RNA sequencing was performed to identify relevant molecular targets genes. Putative miRNA target genes were identified through bioinformatics and confirmed through qPCR, Western blotting, and dual-luciferase reporter assays. Peripheral blood samples were collected to isolate serum and endothelial colony-forming cells (ECFCs) in order to measure miR-205, NOTCH2, and angiogenic cytokines expression levels. Lentiviral constructs were then used to inhibit or overexpress miR-205 and NOTCH2 in isolated ECFCs, after which the angiogenic activity of these cells was evaluated in migration, wound healing, proliferation, tube formation, and chick chorioallantoic membrane (CAM) assay. Autologous ECFCs transfected to knockdown miR-205 and were injected directly into the distraction callus. On days 14, 28, 35 and 42 after surgery, bone density was evaluated via CBCT, and callus samples were collected and evaluated via histological staining to analyze bone regeneration and remodeling. Results MiR-205 was identified as being one of the miRNAs that was most significantly downregulated in MDO callus samples. Downregulation of miR-205 was also observed in DO-ECFCs and serum of animals undergoing MDO. Inhibiting miR-205 markedly enhanced angiogenesis, whereas overexpressing miR-205 had the opposite effect in vitro. Importantly, NOTCH2, which is a unique regulator in bone angiogenesis, was identified as a miR-205 target gene. Consistent with this regulatory relationship, knocking down NOTCH2 suppressed angiogenesis, and transduction with a miR-205 inhibitor lentivirus was sufficient to rescue angiogenic activity. When ECFCs in which miR-205 had been inhibited were transplanted into the MDO callus, this significantly bolstered osteogenesis, and remodeling in vivo. Conclusions MiR-205 is a significant regulator of the MDO process, and inhibiting this miRNA can accelerate MDO-related mineralization. Overall, these results offer new insights into the mechanistic basis for this procedure, highlighting potential targets for therapeutic clinical intervention. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02150-x.
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Affiliation(s)
- Weidong Jiang
- Guangxi Medical University, Nanning, 530021, People's Republic of China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
| | - Peiqi Zhu
- Guangxi Medical University, Nanning, 530021, People's Republic of China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
| | - Tao Zhang
- Guangxi Medical University, Nanning, 530021, People's Republic of China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
| | - Fengchun Liao
- Guangxi Medical University, Nanning, 530021, People's Republic of China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
| | - Yangyang Yu
- Guangxi Medical University, Nanning, 530021, People's Republic of China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
| | - Yan Liu
- Guangxi Medical University, Nanning, 530021, People's Republic of China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
| | - Huijuan Shen
- Guangxi Medical University, Nanning, 530021, People's Republic of China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
| | - Zhenchen Zhao
- Guangxi Medical University, Nanning, 530021, People's Republic of China.,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China.,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China
| | - Xuanping Huang
- Guangxi Medical University, Nanning, 530021, People's Republic of China. .,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China. .,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China.
| | - Nuo Zhou
- Guangxi Medical University, Nanning, 530021, People's Republic of China. .,Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guangxi Medical University, Nanning, 530021, People's Republic of China. .,Guangxi Key Laboratory of Oral and Maxillofacial Rehabilitation and Reconstruction, Guangxi Key Laboratory of Oral and Maxillofacial Surgery Disease Treatment, Guangxi Clinical Research Center for Craniofacial Deformity, Nanning, 530021, People's Republic of China.
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11
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Shen Z, Chen Z, Li Z, Zhang Y, Jiang T, Lin H, Huang M, Chen H, Feng J, Jiang Z. Total Flavonoids of Rhizoma Drynariae Enhances Angiogenic-Osteogenic Coupling During Distraction Osteogenesis by Promoting Type H Vessel Formation Through PDGF-BB/PDGFR-β Instead of HIF-1α/ VEGF Axis. Front Pharmacol 2020; 11:503524. [PMID: 33328980 PMCID: PMC7729076 DOI: 10.3389/fphar.2020.503524] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 10/29/2020] [Indexed: 01/10/2023] Open
Abstract
Background: Total flavonoids of Rhizoma Drynariae (TFRD), extracted from the kidney-tonifying traditional Chinese medicine Rhizoma Rrynariae, has been proved to be effective in treating osteoporosis, bone fractures and defects. However, pharmacological effects of TFRD on type H vessels, angiogenic-osteogenic coupling in distraction osteogenesis (DO) and the mechanism remain unclear. This study aims at investigating whether type H vessels exist in the DO model, effects of TFRD on angiogenic-osteogenic coupling and further elucidating the underlying mechanism. Methods: Rats models of DO and bone fracture (FR) were established, and then were separately divided into TFRD and control subgroups. Imageological and histological analyses were performed to assess bone and vessel formation. Immunofluorescent staining of CD31 and endomucin (Emcn) was conducted to determine type H vessel formation. Matrigel tube formation, ALP and Alizarin Red S staining assays were performed to test the effects of TFRD on angiogenesis or osteogenesis of endothelial precursor cells (EPCs) or bone marrow-derived mesenchymal stem cells (BMSCs). Additionally, expression levels of HIF-1α, VEGF, PDGF-BB, RUNX2 and OSX were determined by ELISA, qPCR or western blot, respectively. Results: The in vivo results indicated more formed type H vessels in DO groups than in FR groups and TFRD obviously increased the abundance of type H vessels. Moreover, groups with higher abundance of type H vessels showed better angiogenesis and osteogenesis outcomes. Further in vitro experiments showed that TFRD significantly promoted while blocking PDGF-BB remarkably suppressed the angiogenic activity of EPCs under stress conditions. The levels of p-AKT and p-ERK1/2, downstream mediators of the PDGF-BB pathway, were up-regulated by TFRD but blocked by function blocking anti-PDGF-BB antibody. In contrast, the activated AKT and ERK1/2 and corresponding tube formation were not affected by the HIF-1α inhibitor. Besides, blocking PDGF-BB inhibited the osteogenic differentiation of the stretched BMSCs, but TFRD enhanced the osteogenic activity of BMSCs and ameliorated the inhibition, with more calcium nodes, higher ALP activity and mRNA and protein levels of RUNX2 and OSX. Conclusion: Type H vessels exist in the DO model and TFRD enhances angiogenic-osteogenic coupling during DO by promoting type H vessel formation via PDGF-BB/PDGFR-β instead of HIF-1α/VEGF axis.
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Affiliation(s)
- Zhen Shen
- Department of Orthopaedics, Kunming Municipal Hospital of Traditional Chinese Medicine, The Third Affiliated Hospital of Yunnan University of Chinese Medicine, Kunming, China
- Department of Orthopaedics, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zehua Chen
- The Fifth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zige Li
- Department of Orthopaedics, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yan Zhang
- Department of Orthopaedics, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Tao Jiang
- The Fifth Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Haixiong Lin
- Department of Orthopaedics, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Minling Huang
- Department of Orthopaedics, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Huamei Chen
- Department of Orthopaedics, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Junjie Feng
- Department of Orthopaedics, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ziwei Jiang
- Department of Orthopaedics, the First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
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12
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Mi J, Xu J, Yao H, Li X, Tong W, Li Y, Dai B, He X, Chow DHK, Li G, Lui KO, Zhao J, Qin L. Calcitonin Gene-Related Peptide Enhances Distraction Osteogenesis by Increasing Angiogenesis. Tissue Eng Part A 2020; 27:87-102. [PMID: 32375579 DOI: 10.1089/ten.tea.2020.0009] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Distraction osteogenesis (DO) is a well-established surgical technique for treating bone defect and limb lengthening. The major drawback of DO is the long treatment period as the external fixator has to be kept in place until consolidation is completed. Calcitonin gene-related peptide (CGRP) has been reported to promote angiogenesis by affecting endothelial progenitor cells (EPCs) in limb ischemia and wound healing. Thus, the goal of this study was to evaluate the angiogenic effect of exogenous CGRP on bone regeneration in a rat DO model. Exogenous CGRP was directly injected into the bone defect after each cycle of distraction in vivo. Microcomputed tomography, biomechanical test, and histological analysis were performed to assess the new bone formation. Angiography and immunofluorescence were performed to assess the formation of blood vessels. CD31+CD144+ EPCs in the bone defect were quantified with flow cytometry. In in vitro study, bone marrow stem cells (BMSCs) were used to investigate the effect of CGRP on EPCs production during endothelial differentiation. Our results showed that CGRP significantly promoted bone regeneration and vessel formation after consolidation. CGRP significantly increased the fraction of CD31+CD144+EPCs and the capillary density in the bone defect at the end of distraction phase. CGRP increased EPC population in the endothelial differentiation of BMSCs in vitro by activating PI3K/AKT signaling pathway. Furthermore, differentiated EPCs rapidly assembled into tube-like structures and promoted osteogenic differentiation of BMSCs. In conclusion, CGRP increased EPC population and promoted blood vessel formation and bone regeneration at the defect region in a DO model. Impact statement Distraction osteogenesis (DO) is a well-established surgical technique for limb lengthening and bone defect. The disadvantage of this technique is that external fixator is needed to be kept in place for about 12 months. This may result in increased risk of infection, financial burden, and negative psychological impacts. In this study, we have injected calcitonin gene-related peptide (CGRP) into the defect region after distraction and found that CGRP enhanced vessel formation and bone regeneration in a rat DO model. This suggests that a controlled delivery system for CGRP could be developed and applied clinically for accelerating bone regeneration in patients with DO.
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Affiliation(s)
- Jie Mi
- Musculoskeletal Research Laboratory, Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Department of Orthopedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.,Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopaedics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiankun Xu
- Musculoskeletal Research Laboratory, Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Department of Orthopedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Hao Yao
- Musculoskeletal Research Laboratory, Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Department of Orthopedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Xisheng Li
- Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Wenxue Tong
- Musculoskeletal Research Laboratory, Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Department of Orthopedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Ye Li
- Musculoskeletal Research Laboratory, Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Department of Orthopedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Bingyang Dai
- Musculoskeletal Research Laboratory, Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Department of Orthopedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Xuan He
- Musculoskeletal Research Laboratory, Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Department of Orthopedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Dick Ho Kiu Chow
- Musculoskeletal Research Laboratory, Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Department of Orthopedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Gang Li
- Musculoskeletal Research Laboratory, Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Department of Orthopedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Kathy O Lui
- Department of Chemical Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Jie Zhao
- Shanghai Key Laboratory of Orthopedic Implants, Department of Orthopaedics, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ling Qin
- Musculoskeletal Research Laboratory, Innovative Orthopedic Biomaterial and Drug Translational Research Laboratory, Department of Orthopedics & Traumatology, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
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An update to the advances in understanding distraction histogenesis: From biological mechanisms to novel clinical applications. J Orthop Translat 2020. [DOI: 10.1016/j.jot.2020.09.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Xing Z, Zhao C, Liu H, Fan Y. Endothelial Progenitor Cell-Derived Extracellular Vesicles: A Novel Candidate for Regenerative Medicine and Disease Treatment. Adv Healthc Mater 2020; 9:e2000255. [PMID: 32378361 DOI: 10.1002/adhm.202000255] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2020] [Revised: 04/12/2020] [Indexed: 12/15/2022]
Abstract
Extracellular vesicles (EVs) are a heterogeneous group of membranous structures, which can be secreted by most cell types. As a product of paracrine secretion, EVs are considered to be a regulatory mediator for intercellular communication. There are many bioactive cargos in EVs, such as proteins, lipids, and nucleic acids. As the precursor cell of vascular endothelial cells (ECs), endothelial progenitor cells (EPCs) are first discovered in peripheral blood. With the development of studies about the functions of EPCs, an increasing number of researchers focus on EPC-derived EVs (EPC-EVs). EPC-EVs exert key functions for promoting angiogenesis in regenerative medicine and show significant therapeutic effects on a variety of diseases such as circulatory diseases, kidney diseases, diabetes, bone diseases, and tissue/organ damages. This article reviews the current knowledge on the role of EPC-EVs in regenerative medicine and disease treatment, discussing the main challenges and future directions in this field.
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Affiliation(s)
- Zheng Xing
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of EducationSchool of Biological Science and Medical EngineeringBeihang University Beijing 100191 P. R. China
| | - Chen Zhao
- School of Pharmaceutical SciencesTsinghua University Beijing 100084 P. R. China
| | - Haifeng Liu
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of EducationSchool of Biological Science and Medical EngineeringBeihang University Beijing 100191 P. R. China
- Beijing Advanced Innovation Centre for Biomedical EngineeringBeihang University Beijing 100191 P. R. China
| | - Yubo Fan
- Key Laboratory for Biomechanics and Mechanobiology of Ministry of EducationSchool of Biological Science and Medical EngineeringBeihang University Beijing 100191 P. R. China
- Beijing Advanced Innovation Centre for Biomedical EngineeringBeihang University Beijing 100191 P. R. China
- National Research Center for Rehabilitation Technical Aids Beijing 100176 P. R. China
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Zhang F, Huan L, Xu T, Li G, Zheng B, Zhao H, Guo Y, Shi J, Sun J, Chen A. Inflammatory macrophages facilitate mechanical stress-induced osteogenesis. Aging (Albany NY) 2020; 12:3617-3625. [PMID: 32096768 PMCID: PMC7066933 DOI: 10.18632/aging.102833] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Accepted: 01/27/2020] [Indexed: 05/17/2023]
Abstract
Mechanical stress has been recognized as a key inducer of bone regeneration in bone damage, which is experimentally mimicked by distraction osteogenesis (DO), a bone-regenerative process induced by post-osteotomy distraction of the surrounding vascularized bone segments, and realized by new bone formation within the distraction gap. The mechanisms that underlie the DO-induced bone regeneration remain poorly understood and a role of macrophages in the process has been inadequately studied. Here, in a mouse model of DO, we showed significant increase in macrophages in the regeneration area. Moreover, in a loss-of-function approach by depleting inflammatory macrophages, the bone regeneration was compromised by assessment of histology and molecular biology. Thus, our study demonstrates the necessary participation of inflammatory macrophages in the process of DO-induced bone regeneration, and suggests that targeting inflammatory macrophages may help to improve clinical bone repair.
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Affiliation(s)
- Fan Zhang
- Department of Orthopedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200001, China
| | - Le Huan
- Department of Orthopedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200001, China
| | - Tao Xu
- Department of Orthopedic Surgery, No. 906 Hospital of the People’s Liberation Army, Ningbo 330212, China
| | - Guozheng Li
- Department of Spine Surgery, LinZhou Hospital of Traditional Chinese Medicine, Linzhou 456550, China
| | - Bing Zheng
- Department of Orthopedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200001, China
| | - Hong Zhao
- Department of Orthopedic Surgery, No. 906 Hospital of the People’s Liberation Army, Ningbo 330212, China
| | - Yongfei Guo
- Department of Orthopedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200001, China
| | - Jiangang Shi
- Department of Orthopedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200001, China
| | - Jingchuan Sun
- Department of Orthopedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200001, China
| | - Aimin Chen
- Department of Orthopedic Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200001, China
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Yellowley CE, Toupadakis CA, Vapniarsky N, Wong A. Circulating progenitor cells and the expression of Cxcl12, Cxcr4 and angiopoietin-like 4 during wound healing in the murine ear. PLoS One 2019; 14:e0222462. [PMID: 31513647 PMCID: PMC6742462 DOI: 10.1371/journal.pone.0222462] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 08/29/2019] [Indexed: 01/16/2023] Open
Abstract
Migration of cells from both local and systemic sources is essential for the inflammatory and regenerative processes that occur during normal wound healing. CXCL12 is considered a critical regulator of CXCR4-positive cell migration during tissue regeneration. In this study, we investigated the expression of Cxcl12 and Cxcr4 during healing of a murine full thickness ear wound. We also investigated the expression of angiopoietin-like 4, which has been shown to participate in wound angiogenesis and reepithelialization. At time points up to 48hrs, complete blood counts were performed using automated hematology analysis, and the numbers of circulating stem and progenitor cells quantified using flow cytometry. Expression of both Cxcr4 and Angptl4 was significantly elevated within 3 days of wounding, and both were strongly expressed in cells of the epidermis. ANGPTL4 protein expression remained elevated in the epithelium through day 14. Cxcl12 expression was increased significantly at day 3, and remained elevated through day 21. Faint Cxcl12 staining was detectable in the epithelium at day 1, and thereafter staining was faint and more generalized. There were significantly fewer circulating total white blood cells and lymphocytes 1hr following ear punching. Similarly, there was a significant early (1hr) reduction in the number of circulating endothelial progenitor cells. Further studies are warranted to investigate whether ANGPTL4 and CXCL12/CXCR4 interact or synergize to facilitate cell recruitment and migration, and to potentiate reepithelialization and wound healing.
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Affiliation(s)
- Clare E Yellowley
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America
| | - Chrisoula A Toupadakis
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America
| | - Natalia Vapniarsky
- Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America
| | - Alice Wong
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, California, United States of America
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Meeson R, Sanghani-Keri A, Coathup M, Blunn G. CXCR4 Antagonism to Treat Delayed Fracture Healing. Tissue Eng Part A 2019; 25:1242-1250. [PMID: 30612520 PMCID: PMC6864747 DOI: 10.1089/ten.tea.2018.0265] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
A significant number of fractures develop nonunion. Stem cell homing is regulated through stromal cell-derived factor 1 (SDF1) and its receptor CXCR4. Stem/progenitor cell populations can be endogenously mobilized by administering growth factors with a pharmacological antagonist of CXCR4, AMD3100, which may be a means to improve fracture healing. A 1.5 mm femoral osteotomy in Wistar rats was stabilized with an external fixator. Rats were pretreated with phosphate buffered saline [PBS(P)], vascular endothelial growth factor [VEGF(V)], insulin-like growth factor-1 [IGF1(I)], or granulocyte colony stimulating factor [GCSF(G)] before AMD3100. A control group (C) did not receive growth factors or AMD3100. Bone formation after 5 weeks was analyzed. Group P had a significant increase in total bone volume (BV) (p = 0.01) and group I in percentage bone in the fracture gap (p = 0.035). Group G showed a decrease in BV. All treated groups had an increase in trabecular thickness. Histology showed decreased cartilage tissue associated with increased bone in groups with improved healing, and increased fibrous tissue in poorly performing groups. Antagonism of SDF1-CXCR4 axis can boost impaired fracture healing. AMD3100 given alone was the most effective means to boost healing, whereas pretreatment with GCSF reduced healing. AMD3100 is likely mobilizing stem cells into the blood stream that home to the fracture site enhancing healing.
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Affiliation(s)
- Richard Meeson
- Division of Surgery, Institute of Orthopaedics and Musculoskeletal Science, University College London, London, United Kingdom.,Department of Clinical Services and Sciences, Royal Veterinary College, Hatfield, United Kingdom
| | - Anita Sanghani-Keri
- Division of Surgery, Institute of Orthopaedics and Musculoskeletal Science, University College London, London, United Kingdom
| | - Melanie Coathup
- Division of Surgery, Institute of Orthopaedics and Musculoskeletal Science, University College London, London, United Kingdom.,University of Central Florida, Orlando, Florida
| | - Gordon Blunn
- Division of Surgery, Institute of Orthopaedics and Musculoskeletal Science, University College London, London, United Kingdom.,University of Portsmouth, Portsmouth, United Kingdom
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Meeson R, Sanghani‐Keri A, Coathup M, Blunn G. VEGF with AMD3100 endogenously mobilizes mesenchymal stem cells and improves fracture healing. J Orthop Res 2019; 37:1294-1302. [PMID: 30345545 PMCID: PMC6563072 DOI: 10.1002/jor.24164] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 10/11/2018] [Indexed: 02/04/2023]
Abstract
A significant number of fractures develop non-union. Mesenchymal stem cell (MSC) therapy may be beneficial, however, this requires cell acquisition, culture and delivery. Endogenous mobilization of stem cells offers a non-invasive alternative. The hypothesis was administration of VEGF and the CXCR4 antagonist AMD3100 would increase the circulating pool of available MSCs and improve fracture healing. Ex-breeder female wistar rats received VEGF followed by AMD3100, or sham PBS. Blood prepared for culture and colonies were counted. P3 cells were analyzed by flow cytometry, bi-differentiation. The effect of mobilization on fracture healing was evaluated with 1.5 mm femoral osteotomy stabilized with an external fixator in 12-14 week old female Wistars. The mobilized group had significantly greater number of cfus/ml compared to controls, p = 0.029. The isolated cells expressed 1.8% CD34, 35% CD45, 61% CD29, 78% CD90, and differentiated into osteoblasts but not into adipocytes. The fracture gap in animals treated with VEGF and AMD3100 showed increased bone volume; 5.22 ± 1.7 µm3 and trabecular thickness 0.05 ± 0.01 µm compared with control animals (4.3 ± 3.1 µm3 , 0.04 ± 0.01 µm, respectively). Radiographic scores quantifying fracture healing (RUST) showed that the animals in the mobilization group had a higher healing score compared to controls (9.6 vs. 7.7). Histologically, mobilization resulted in significantly lower group variability in bone formation (p = 0.032) and greater amounts of bone and less fibrous tissue than the control group. Clinical significance: This pre-clinical study demonstrates a beneficial effect of endogenous MSC mobilization on fracture healing, which may have translation potential to prevent or treat clinical fractures at risk of delayed or non-union fractures. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:1294-1302, 2019.
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Affiliation(s)
- Richard Meeson
- Division of SurgeryUniversity College LondonStanmoreUnited Kingdom,Royal Veterinary CollegeHertfordshireUnited Kingdom
| | | | - Melanie Coathup
- Division of SurgeryUniversity College LondonStanmoreUnited Kingdom,University of Central FloridaFlorida
| | - Gordon Blunn
- Division of SurgeryUniversity College LondonStanmoreUnited Kingdom,University of PortsmouthPortsmouthUnited Kingdom
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Jia Y, Zhu Y, Qiu S, Xu J, Chai Y. Exosomes secreted by endothelial progenitor cells accelerate bone regeneration during distraction osteogenesis by stimulating angiogenesis. Stem Cell Res Ther 2019; 10:12. [PMID: 30635031 PMCID: PMC6329174 DOI: 10.1186/s13287-018-1115-7] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Revised: 12/11/2018] [Accepted: 12/18/2018] [Indexed: 01/17/2023] Open
Abstract
Background Distraction osteogenesis (DO) is an effective but lengthy procedure to fully induce bone regeneration in large bone defects. Accumulating evidence supports the role of exosomes secreted by endothelial progenitor cells (EPC-Exos) in stimulating angiogenesis, which is closely coupled with osteogenesis. This study aimed to investigate whether EPC-Exos promote bone regeneration during DO in rats. Methods Exosomes were isolated from the supernatants of rat bone marrow EPCs via ultracentrifugation and characterized via transmission electron microscopy, tunable resistive pulse sensing analysis, and western blot analysis. Unilateral tibial DO models were generated using 68 Sprague-Dawley rats with a distraction rate of 0.5 mm per day for 10 days. After local injection of EPC-Exos into the distraction gaps after distraction, the therapeutic effects of EPC-Exos on bone regeneration and angiogenesis were assessed via X-ray, micro-computed tomography (micro-CT), and biomechanical and histological analyses. Pro-angiogenic effects and the potential mechanism underlying the effects of EPC-Exos on human umbilical vein endothelial cells were subsequently evaluated via in vitro assays including Cell Counting Kit-8, wound healing, tube formation, and western blot assays. Results EPC-Exos were spherical or cup-shaped vesicles ranging from 50 to 150 nm in diameter and expressed markers including CD9, Alix, and TSG101. X-ray, micro-CT, and histological analyses revealed that bone regeneration was markedly accelerated in rats treated with EPC-Exos. The distracted tibias from the Exos group also displayed enhanced mechanical properties. Moreover, vessel density was higher in the Exos group than in the control group. In addition, in vitro analyses revealed that EPC-Exos enhanced the proliferation, migration, and angiogenic capacity of endothelial cells in an miR-126-dependent manner. Further, EPC-Exos downregulated SPRED1 and activated Raf/ERK signaling. Conclusions The present results show that EPC-Exos accelerate bone regeneration during DO by stimulating angiogenesis, suggesting their use as a novel method to shorten the treatment duration of DO.
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Affiliation(s)
- Yachao Jia
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Yishan Rd 600, Shanghai, 200233, People's Republic of China
| | - Yu Zhu
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Yishan Rd 600, Shanghai, 200233, People's Republic of China
| | - Shuo Qiu
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Yishan Rd 600, Shanghai, 200233, People's Republic of China
| | - Jia Xu
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Yishan Rd 600, Shanghai, 200233, People's Republic of China.
| | - Yimin Chai
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Yishan Rd 600, Shanghai, 200233, People's Republic of China.
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20
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Shen J, Ye X. [Effect of "accordion" technique on bone consolidation during distraction osteogenesis]. ZHONGGUO XIU FU CHONG JIAN WAI KE ZA ZHI = ZHONGGUO XIUFU CHONGJIAN WAIKE ZAZHI = CHINESE JOURNAL OF REPARATIVE AND RECONSTRUCTIVE SURGERY 2018; 32:558-567. [PMID: 29806343 PMCID: PMC8430005 DOI: 10.7507/1002-1892.201712094] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 03/30/2018] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To investigate the effect, right timing, and mechanism of "accordion" technique on bone regeneration in rat distraction osteogenesis model. METHODS Fifty-four 12-week-old male Sprague Dawley rats underwent right tibial distraction osteogenesis procedure. After a 5-day latency, the distraction was performed for 7 days followed by 6-week consolidation. All animals were randomly divided into 4 groups based on different periods of "accordion" maneuvers in consolidation phase: control group ( n=18) with no manipulation, and three experimental groups including early-phase group ( n=18), mid-phase group ( n=12), and late-phase group ( n=6) with "accordion" maneuvers applied at 1, 3, and 5 weeks, respectively. The duration of the "accordion" maneuver was 7 days consisting of a 3.5-day compression and 3.5-day distraction. Rats in control group and early-phase group were sacrificed at 2, 4, and 6 weeks of the consolidation phase; rats in mid-phase group were sacrificed at 4 and 6 weeks of the consolidation phase; and rats in late-phase group were sacrificed at 6 weeks of the consolidation phase. Bilateral tibias from 6 rats in each group at each time point were obtained. Callus formation was monitored by X-ray radiography every week; new bone was reconstructed by Micro-CT three-dimensional reconstruction. The change of bone structure was evaluated, and parameters containing bone volume (BV)/tissue volume (TV) ratio (BV/TV) and bone mineral density (BMD) in three thresholds (158-211, 211-1 000, 158-1 000) were recorded and calculated at 6 weeks. Mechanical test consisting of ultimate load, modulus of elasticity, and energy to failure was performed. Histological analysis, such as Von Kossa staining, Safranin O staining, and HE staining, was done. Immunohistochemical staining using markers of osterix (OSX), osteocalcin (OCN), and vascular endothelial growth factor (VEGF) was analyzed. RESULTS Images of X-ray showed that callus formation increased significantly in the mid-phase group. Micro-CT three-dimensional reconstruction demonstrated the mid-phase group owned fastest reconstructed speed among 4 groups, the cortical bone was continual at 6 weeks. At 6 weeks, the BMD and BV/TV in thresholds 158-1 000 and 211-1 000 in mid-phase group were higher than those in other groups. The results of mechanical test showed that ultimate load, modulus of elasticity, and energy to failure in mid-phase group were significantly higher than those in other groups ( P<0.05). Histological testing showed that the continuity of bone marrow cavity in mid-phase group was evident at 6 weeks after distraction. Immunohistochemical analyses confirmed the expression levels of osteogenesis (OCN, OSX) and angiogenesis (VEGF) elevated remarkably and then returned to normal in mid-phase group. CONCLUSION The "accordion" technique is beneficial for new callus formation in distraction area. Applying the maneuver during the middle phase of the consolidation period was effective to accelerate new bone formation in rat distraction osteogenesis model.
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Affiliation(s)
- Jie Shen
- Department of Orthopedics, Changzheng Hospital, the Second Military Medical University, Shanghai, 200003, P.R.China
| | - Xiaojian Ye
- Department of Orthopedics, Changzheng Hospital, the Second Military Medical University, Shanghai, 200003,
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Xu J, Sun Y, Wu T, Liu Y, Shi L, Zhang J, Kang Q, Chai Y, Li G. Enhancement of bone regeneration with the accordion technique via HIF-1α/VEGF activation in a rat distraction osteogenesis model. J Tissue Eng Regen Med 2017; 12:e1268-e1276. [PMID: 28763580 DOI: 10.1002/term.2534] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 07/05/2017] [Accepted: 07/27/2017] [Indexed: 11/05/2022]
Abstract
Axial micromotion of bone fragments promotes callus formation and bone healing during the process of distraction osteogenesis (DO). This study investigated the effects of the combined axial compression and distraction (accordion) technique on bone regeneration in rat DO model. Male Sprague-Dawley rats (n = 62) underwent right tibial transverse osteotomy and were randomly divided into four groups after lengthening: control (no manipulation) and three experimental groups assigned on the basis of the period of accordion manoeuvres in the consolidation phase (Groups 1, 2, and 3 with accordion technique applied at Weeks 1, 3, and 5, respectively). Animals were terminated at 1 week after each accordion phase (i.e., Weeks 2, 4, and 6). Callus formation was monitored by X-ray radiography; new bone quality was evaluated by microcomputed tomography, histological analysis, and mechanical testing. Serum levels of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) were measured. Callus formation after accordion manoeuvre at Week 3 (Group 2) increased significantly over time of consolidation. The microcomputed tomography and mechanical analysis revealed Group 2 had more newly formed bone and superior mechanical properties in contrast to the other groups at termination. Histomorphological and immunohistochemical analyses confirmed a greater degree of osteogenesis and angiogenesis corresponding to increased serum levels of HIF-1α and VEGF in Group 2. The accordion technique was effective in promoting bone consolidation via activation of HIF-1α/VEGF during DO. The accordion technique may be used in the middle phase of bone consolidation to promote bone formation in patients undergoing DO treatment.
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Affiliation(s)
- Jia Xu
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Yuxin Sun
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Tianyi Wu
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.,Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Yang Liu
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Liu Shi
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Jinfang Zhang
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Qinglin Kang
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Yimin Chai
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Gang Li
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong
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Zhao B, Zhao Z, Sun X, Zhang Y, Guo Y, Tian P, Ma J, Ma X. Effect of micro strain stress on proliferation of endothelial progenitor cells in vitro by the MAPK-ERK1/2 signaling pathway. Biochem Biophys Res Commun 2017; 492:206-211. [DOI: 10.1016/j.bbrc.2017.08.050] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 08/13/2017] [Indexed: 10/19/2022]
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Xu J, Chen Y, Liu Y, Zhang J, Kang Q, Ho K, Chai Y, Li G. Effect of SDF-1/Cxcr4 Signaling Antagonist AMD3100 on Bone Mineralization in Distraction Osteogenesis. Calcif Tissue Int 2017; 100:641-652. [PMID: 28303319 DOI: 10.1007/s00223-017-0249-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 01/30/2017] [Indexed: 01/16/2023]
Abstract
Distraction osteogenesis (DO) is a widely applied technique in orthopedics surgery, which involves rapid stem cell migration, homing, and differentiation. Interactions between the chemokine receptor Cxcr4 and its ligand, stromal derived factor-1 (SDF-1), regulate hematopoietic stem cell trafficking to the ischemic area and induce their subsequent differentiation. Here, we examined SDF-1 expression and further investigated the role of SDF-1/Cxcr4 signaling antagonist AMD3100 during bone regeneration in rat DO model. The results showed that expression levels of SDF-1 and osteogenic genes were higher in DO zones than in the fracture zones, and SDF-1 expression level was the highest at the termination of the distraction phase. Radiological, mechanical, and histological analyses demonstrated that the local administration of AMD3100 (400 μM) to DO rats significantly inhibited new bone formation. In the rat bone marrow mesenchymal stem cells culture, comparing to the group treated with osteogenic induction medium, AMD3100 supplement led to a considerable decrease in the expression of alkaline phosphatase and early osteogenic marker genes. However, the amount of calcium deposits in rat MSCs did not differ between the groups. Therefore, our study demonstrated that the DO process induced higher expression of SDF-1, which collated to rapid induction of callus formation. Local application of SDF-1/Cxcr4 signaling antagonist AMD3100 significantly inhibited bone mineralization and osteogenesis in DO, which may represent a potential therapeutic approach to the enhancement of bone consolidation in patients undergoing DO.
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Affiliation(s)
- Jia Xu
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
| | - Yuanfeng Chen
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Room 904, 9/F, Shatin, Hong Kong Sar, People's Republic of China
- Institute of Orthopedic Diseases and Department of Orthopedics, the First Affiliated Hospital, Jinan University, Guangzhou, People's Republic of China
| | - Yang Liu
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Room 904, 9/F, Shatin, Hong Kong Sar, People's Republic of China
| | - Jinfang Zhang
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Room 904, 9/F, Shatin, Hong Kong Sar, People's Republic of China
| | - Qinglin Kang
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China
| | - Kiwai Ho
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Room 904, 9/F, Shatin, Hong Kong Sar, People's Republic of China
| | - Yimin Chai
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
| | - Gang Li
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, Prince of Wales Hospital, The Chinese University of Hong Kong, Room 904, 9/F, Shatin, Hong Kong Sar, People's Republic of China.
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Zigdon-Giladi H, Elimelech R, Michaeli-Geller G, Rudich U, Machtei EE. Safety profile and long-term engraftment of human CD31 + blood progenitors in bone tissue engineering. Cytotherapy 2017; 19:895-908. [PMID: 28495397 DOI: 10.1016/j.jcyt.2017.03.079] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 03/23/2017] [Accepted: 03/24/2017] [Indexed: 02/08/2023]
Abstract
BACKGROUND Endothelial progenitor cells (EPCs) participate in angiogenesis and induce favorable micro-environments for tissue regeneration. The efficacy of EPCs in regenerative medicine is extensively studied; however, their safety profile remains unknown. Therefore, our aims were to evaluate the safety profile of human peripheral blood-derived EPCs (hEPCs) and to assess the long-term efficacy of hEPCs in bone tissue engineering. METHODS hEPCs were isolated from peripheral blood, cultured and characterized. β tricalcium phosphate scaffold (βTCP, control) or 106 hEPCs loaded onto βTCP were transplanted in a nude rat calvaria model. New bone formation and blood vessel density were analyzed using histomorphometry and micro-computed tomography (CT). Safety of hEPCs using karyotype analysis, tumorigenecity and biodistribution to target organs was evaluated. RESULTS On the cellular level, hEPCs retained their karyotype during cell expansion (seven passages). Five months following local hEPC transplantation, on the tissue and organ level, no inflammatory reaction or dysplastic change was evident at the transplanted site or in distant organs. Direct engraftment was evident as CD31 human antigens were detected lining vessel walls in the transplanted site. In distant organs human antigens were absent, negating biodistribution. Bone area fraction and bone height were doubled by hEPC transplantation without affecting mineral density and bone architecture. Additionally, local transplantation of hEPCs increased blood vessel density by nine-fold. CONCLUSIONS Local transplantation of hEPCs showed a positive safety profile. Furthermore, enhanced angiogenesis and osteogenesis without mineral density change was found. These results bring us one step closer to first-in-human trials using hEPCs for bone regeneration.
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Affiliation(s)
- Hadar Zigdon-Giladi
- Department of Periodontology, School of Graduate Dentistry, Rambam Health Care Campus, Haifa, Israel; Research Institute for Bone Repair, Rambam Health Care Campus, Haifa, Israel; The Rappaport Family Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.
| | - Rina Elimelech
- Department of Periodontology, School of Graduate Dentistry, Rambam Health Care Campus, Haifa, Israel; Research Institute for Bone Repair, Rambam Health Care Campus, Haifa, Israel
| | - Gal Michaeli-Geller
- Research Institute for Bone Repair, Rambam Health Care Campus, Haifa, Israel
| | - Utai Rudich
- Orthopedic Department, Rambam Health Care Campus, Haifa, Israel
| | - Eli E Machtei
- Department of Periodontology, School of Graduate Dentistry, Rambam Health Care Campus, Haifa, Israel; Research Institute for Bone Repair, Rambam Health Care Campus, Haifa, Israel; The Rappaport Family Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
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The Use of Endothelial Progenitor Cells for the Regeneration of Musculoskeletal and Neural Tissues. Stem Cells Int 2017; 2017:1960804. [PMID: 28458693 PMCID: PMC5387841 DOI: 10.1155/2017/1960804] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Accepted: 03/12/2017] [Indexed: 12/18/2022] Open
Abstract
Endothelial progenitor cells (EPCs) derived from bone marrow and blood can differentiate into endothelial cells and promote neovascularization. In addition, EPCs are a promising cell source for the repair of various types of vascularized tissues and have been used in animal experiments and clinical trials for tissue repair. In this review, we focused on the kinetics of endogenous EPCs during tissue repair and the application of EPCs or stem cell populations containing EPCs for tissue regeneration in musculoskeletal and neural tissues including the bone, skeletal muscle, ligaments, spinal cord, and peripheral nerves. EPCs can be mobilized from bone marrow and recruited to injured tissue to contribute to neovascularization and tissue repair. In addition, EPCs or stem cell populations containing EPCs promote neovascularization and tissue repair through their differentiation to endothelial cells or tissue-specific cells, the upregulation of growth factors, and the induction and activation of endogenous stem cells. Human peripheral blood CD34(+) cells containing EPCs have been used in clinical trials of bone repair. Thus, EPCs are a promising cell source for the treatment of musculoskeletal and neural tissue injury.
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Xu J, Wang B, Sun Y, Wu T, Liu Y, Zhang J, Lee WY, Pan X, Chai Y, Li G. Human fetal mesenchymal stem cell secretome enhances bone consolidation in distraction osteogenesis. Stem Cell Res Ther 2016; 7:134. [PMID: 27612565 PMCID: PMC5018171 DOI: 10.1186/s13287-016-0392-2] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 08/17/2016] [Accepted: 08/23/2016] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Distraction osteogenesis (DO) is one of the most dramatic reconstructive techniques for inducing bone regeneration, but it involves an undesirably long period for bone consolidation. Developing innovative approaches to enhance bone consolidation is a burning need. Human fetal mesenchymal stem cells (hFMSCs) have been shown to express more primitive developmental genes than those of human adult mesenchymal stem cells (hAMSCs), which is a preferable source for cell therapy and tissue regeneration. In the present study, we investigated the immunogenicity of using the human mesenchymal stem cell (MSC) secretome on rat cells, the effects of secretome on osteogenic differentiation of rat bone marrow-derived MSCs (rBMSCs), and the potential application of hFMSC secretome in promoting bone consolidation in a rat DO model. METHODS Secretome was collected from MSC culture and was used to treat rBMSCs. Following secretome treatment, cell proliferation, alkaline phosphatase staining, Alizarin Red S staining, and mRNA expression of osteogenic differentiation-related genes (including ALP, Runx2, OCN, OPN, and Osx) in the rBMSCs were checked, as well as mixed rat peripheral blood lymphocyte reaction. hFMSC secretome was injected locally into the regenerates from the end of lengthening every 3 days in the rat DO model, until termination. The regenerates were subject to weekly x-rays, micro-computed tomography (μCT) and mechanical testing examination. The bone quality was assessed by histology and immunohistochemistry examinations. RESULTS Compared to the secretome from rBMSCs and hAMSCs, hFMSC secretome had the best osteogenic induction ability and low immunogenicity. hFMSC secretome with different doses showed no effect on cell viability. hFMSC secretome at the dose of 100 μg/μl could significantly increase the expression of alkaline phosphatase and all the osteogenic marker genes, as well as the amount of calcium deposits in the rBMSCs. Finally, the local application of hFMSC secretome in distraction regenerates in a rat DO model significantly improved bone consolidation according to the results of μCT, mechanical test, and histological and immunohistochemistry analysis. CONCLUSIONS The current study demonstrated that hFMSC secretome promotes osteogenesis of rBMSCs and bone consolidation during DO. hFMSC secretome may be a new therapeutic strategy to enhance bone consolidation in patients undergoing DO treatment.
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Affiliation(s)
- Jia Xu
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.,Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, People's Republic of China
| | - Bin Wang
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, People's Republic of China
| | - Yuxin Sun
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, People's Republic of China
| | - Tianyi Wu
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, People's Republic of China
| | - Yang Liu
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, People's Republic of China
| | - Jinfang Zhang
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, People's Republic of China.,The CUHK-ACC Space Medicine Centre, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, People's Republic of China
| | - Wayne Yukwai Lee
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, People's Republic of China
| | - Xiaohua Pan
- Department of Orthopaedics and Traumatology, Bao-An People's Hospital, Shenzhen, People's Republic of China
| | - Yimin Chai
- Department of Orthopaedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
| | - Gang Li
- Department of Orthopaedics & Traumatology, Stem Cells and Regeneration Laboratory, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, SAR, People's Republic of China. .,The CUHK-ACC Space Medicine Centre, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, People's Republic of China. .,Department of Orthopaedics and Traumatology, Bao-An People's Hospital, Shenzhen, People's Republic of China.
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Okada K, Kawao N, Yano M, Tamura Y, Kurashimo S, Okumoto K, Kojima K, Kaji H. Stromal cell-derived factor-1 mediates changes of bone marrow stem cells during the bone repair process. Am J Physiol Endocrinol Metab 2016; 310:E15-23. [PMID: 26530150 DOI: 10.1152/ajpendo.00253.2015] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Accepted: 10/27/2015] [Indexed: 12/11/2022]
Abstract
Osteoblasts, osteoclasts, chondrocytes, and macrophages that participate in the bone repair process are derived from hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). However, the roles of these stem cells during the repair of injured bone tissue are still unclear. In the present study, we examined the effects of bone defect on HSCs and MSCs in bone marrow and spleen in 75 mice and its mechanism. We analyzed the HSC and MSC populations in these tissues of a mouse with femoral bone damage by using flow cytometry. The number of HSCs in the bone marrow of mice with damaged femurs was significantly lower than the number of these cells in the bone marrow of the contralateral intact femurs on day 2 after injury. Meanwhile, the number of MSCs in the bone marrow of mice with damaged femurs was significantly higher than that of the contralateral femurs. Both intraperitoneal administration of AMD3100, a C-X-C chemokine receptor 4 (CXCR4) antagonist, and local treatment with an anti-stromal cell-derived factor-1 (SDF-1) antibody blunted the observed decrease in HSC and increase in MSC populations within the bone marrow of injured femurs. In conclusion, the present study revealed that there is a concurrent decrease and increase in the numbers of HSCs and MSCs, respectively, in the bone marrow during repair of mouse femoral bone damage. Furthermore, the SDF-1/CXCR4 system was implicated as contributing to the changes in these stem cell populations upon bone injury.
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Affiliation(s)
- Kiyotaka Okada
- Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan; and
| | - Naoyuki Kawao
- Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan; and
| | - Masato Yano
- Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan; and
| | - Yukinori Tamura
- Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan; and
| | - Shinzi Kurashimo
- Life Science Research Institute, Kinki University, Osakasayama, Osaka, Japan
| | - Katsumi Okumoto
- Life Science Research Institute, Kinki University, Osakasayama, Osaka, Japan
| | - Kotarou Kojima
- Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan; and
| | - Hiroshi Kaji
- Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osakasayama, Osaka, Japan; and
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Myers TJ, Longobardi L, Willcockson H, Temple JD, Tagliafierro L, Ye P, Li T, Esposito A, Moats-Staats BM, Spagnoli A. BMP2 Regulation of CXCL12 Cellular, Temporal, and Spatial Expression is Essential During Fracture Repair. J Bone Miner Res 2015; 30:2014-27. [PMID: 25967044 PMCID: PMC4970512 DOI: 10.1002/jbmr.2548] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Revised: 04/27/2015] [Accepted: 05/05/2015] [Indexed: 12/30/2022]
Abstract
The cellular and humoral responses that orchestrate fracture healing are still elusive. Here we report that bone morphogenic protein 2 (BMP2)-dependent fracture healing occurs through a tight control of chemokine C-X-C motif-ligand-12 (CXCL12) cellular, spatial, and temporal expression. We found that the fracture repair process elicited an early site-specific response of CXCL12(+)-BMP2(+) endosteal cells and osteocytes that was not present in unfractured bones and gradually decreased as healing progressed. Absence of a full complement of BMP2 in mesenchyme osteoprogenitors (BMP2(cKO/+)) prevented healing and led to a dysregulated temporal and cellular upregulation of CXCL12 expression associated with a deranged angiogenic response. Healing was rescued when BMP2(cKO/+) mice were systemically treated with AMD3100, an antagonist of CXCR4 and agonist for CXCR7 both receptors for CXCL12. We further found that mesenchymal stromal cells (MSCs), capable of delivering BMP2 at the endosteal site, restored fracture healing when transplanted into BMP2(cKO/+) mice by rectifying the CXCL12 expression pattern. Our in vitro studies showed that in isolated endosteal cells, BMP2, while inducing osteoblastic differentiation, stimulated expression of pericyte markers that was coupled with a decrease in CXCL12. Furthermore, in isolated BMP2(cKO/cKO) endosteal cells, high expression levels of CXCL12 inhibited osteoblastic differentiation that was restored by AMD3100 treatment or coculture with BMP2-expressing MSCs that led to an upregulation of pericyte markers while decreasing platelet endothelial cell adhesion molecule (PECAM). Taken together, our studies show that following fracture, a CXCL12(+)-BMP2(+) perivascular cell population is recruited along the endosteum, then a timely increase of BMP2 leads to downregulation of CXCL12 that is essential to determine the fate of the CXCL12(+)-BMP2(+) to osteogenesis while departing their supportive role to angiogenesis. Our findings have far-reaching implications for understanding mechanisms regulating the selective recruitment of distinct cells into the repairing niches and the development of novel pharmacological (by targeting BMP2/CXCL12) and cellular (MSCs, endosteal cells) interventions to promote fracture healing.
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Affiliation(s)
- Timothy J Myers
- Division of Endocrinology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Lara Longobardi
- Division of Endocrinology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Helen Willcockson
- Division of Endocrinology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Joseph D Temple
- Division of Endocrinology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA
| | - Lidia Tagliafierro
- Division of Endocrinology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Ping Ye
- Division of Endocrinology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Tieshi Li
- Division of Endocrinology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA
| | - Alessandra Esposito
- Division of Endocrinology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA
| | - Billie M Moats-Staats
- Division of Endocrinology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Anna Spagnoli
- Division of Endocrinology, Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.,Department of Pediatrics, Rush University Medical Center, Chicago, IL, USA
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Zigdon-Giladi H, Rudich U, Michaeli Geller G, Evron A. Recent advances in bone regeneration using adult stem cells. World J Stem Cells 2015; 7:630-640. [PMID: 25914769 PMCID: PMC4404397 DOI: 10.4252/wjsc.v7.i3.630] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2014] [Revised: 12/30/2014] [Accepted: 01/20/2015] [Indexed: 02/06/2023] Open
Abstract
Bone is a highly vascularized tissue reliant on the close spatial and temporal association between blood vessels and bone cells. Therefore, cells that participate in vasculogenesis and osteogenesis play a pivotal role in bone formation during prenatal and postnatal periods. Nevertheless, spontaneous healing of bone fracture is occasionally impaired due to insufficient blood and cellular supply to the site of injury. In these cases, bone regeneration process is interrupted, which might result in delayed union or even nonunion of the fracture. Nonunion fracture is difficult to treat and have a high financial impact. In the last decade, numerous technological advancements in bone tissue engineering and cell-therapy opened new horizon in the field of bone regeneration. This review starts with presentation of the biological processes involved in bone development, bone remodeling, fracture healing process and the microenvironment at bone healing sites. Then, we discuss the rationale for using adult stem cells and listed the characteristics of the available cells for bone regeneration. The mechanism of action and epigenetic regulations for osteogenic differentiation are also described. Finally, we review the literature for translational and clinical trials that investigated the use of adult stem cells (mesenchymal stem cells, endothelial progenitor cells and CD34+ blood progenitors) for bone regeneration.
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30
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Piatkowski A, Grieb G, Simons D, Bernhagen J, van der Hulst RR. Endothelial progenitor cells--potential new avenues to improve neoangiogenesis and reendothelialization. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2014; 306:43-81. [PMID: 24016523 DOI: 10.1016/b978-0-12-407694-5.00002-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The term endothelial progenitor cell (EPC) was established more than 10 years ago and is used to refer to a group of circulating cells that display endothelial lineage qualities and are able to home to areas of ischemia or vascular injury and to facilitate the repair of damaged blood vessels or develop new vessels as needed. This chapter reviews the current lineage relationships among all the cells called EPC and will clear the terminology used in EPC research. Furthermore, an overview of the clinical and in vitro research, as well as cytokine and drug interactions and potential EPC applications, is given.
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Affiliation(s)
- Andrzej Piatkowski
- Department of Plastic Surgery, academisch ziekenhuis Maastricht, MUMC+, Maastricht, The Netherlands.
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Kuroda R, Matsumoto T, Niikura T, Kawakami Y, Fukui T, Lee SY, Mifune Y, Kawamata S, Fukushima M, Asahara T, Kawamoto A, Kurosaka M. Local transplantation of granulocyte colony stimulating factor-mobilized CD34+ cells for patients with femoral and tibial nonunion: pilot clinical trial. Stem Cells Transl Med 2014; 3:128-34. [PMID: 24307697 PMCID: PMC3902290 DOI: 10.5966/sctm.2013-0106] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Most bone fractures typically heal, although a significant proportion (5%-10%) of fractures fail to heal, resulting in delayed union or persistent nonunion. Some preclinical evidence shows the therapeutic potential of peripheral blood CD34(+) cells, a hematopoietic/endothelial progenitor cell-enriched population, for bone fracture healing; however, clinical outcome following transplantation of CD34(+) cells in patients with fracture has never been reported. We report a phase I/IIa clinical trial regarding transplantation of autologous, granulocyte colony stimulating factor-mobilized CD34(+) cells with atelocollagen scaffold for patients with femoral or tibial fracture nonunion (n = 7). The primary endpoint of this study is radiological fracture healing (union) by evaluating anteroposterior and lateral views at week 12 following cell therapy. For the safety evaluation, incidence, severity, and outcome of all adverse events were recorded. Radiological fracture healing at week 12 was achieved in five of seven cases (71.4%), which was greater than the threshold (18.1%) predefined by the historical outcome of the standard of care. The interval between cell transplantation and union, the secondary endpoint, was 12.6 ± 5.4 weeks (range, 8-24 weeks) for clinical healing and 16.1 ± 10.2 weeks (range, 8-36 weeks) for radiological healing. Neither deaths nor life-threatening adverse events were observed during the 1-year follow-up after the cell therapy. These results suggest feasibility, safety, and potential effectiveness of CD34(+) cell therapy in patients with nonunion.
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Stogov MV, Luneva SN, Novikov KI. Growth factors in human serum during operative tibial lengthening with the Ilizarov method. J Orthop Res 2013; 31:1966-1970. [PMID: 23893880 DOI: 10.1002/jor.22454] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Accepted: 07/05/2013] [Indexed: 02/04/2023]
Abstract
Despite the widespread clinical use of distraction osteogenesis for limb lengthening, the cellular and molecular mechanisms by which this surgical treatment promotes new bone formation in humans are not well understood. The aim of the research was to study the levels of growth factors (GFs) in the serum of patients that were undergoing tibial lengthening with the Ilizarov method of distraction osteogenesis. Those were patients with unilateral congenital discrepancy of the tibia (n = 12), unilateral posttraumatic tibial shortening (n = 7), and healthy patients that underwent cosmetic bilateral tibial lengthening (n = 10). The study established that unlike the congenital group, the posttraumatic group and healthy subjects showed a significantly evident increase in the levels of angiogenic GFs in their serum on day 10 of distraction. In the congenital group, the changes were not significant at this time point. The levels of TGF-α, TGF-β1, and TGF-β2 tended to decrease on day 10 of distraction and on day 30 of the post-distraction period in the cosmetic and posttraumatic groups while they grew in the congenital group. Most dynamic changes in the GFs levels during tibial lengthening were noted in the subjects undergoing cosmetic lengthening, and the least ones were in the congenital group.
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Affiliation(s)
- Maksim V Stogov
- Clinical and Experimental Laboratory Department, Russian Ilizarov Scientific Center for Restorative Traumatology and Orthopedics, 6, M. Ulianova Street, 640014, Kurgan, Russian Federation
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Seo SG, Yeo JH, Kim JH, Kim JB, Cho TJ, Lee DY. Negative-pressure wound therapy induces endothelial progenitor cell mobilization in diabetic patients with foot infection or skin defects. Exp Mol Med 2013; 45:e62. [PMID: 24232261 PMCID: PMC3849576 DOI: 10.1038/emm.2013.129] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Revised: 08/17/2013] [Accepted: 09/02/2013] [Indexed: 02/06/2023] Open
Abstract
Non healing chronic wounds are difficult to treat in patients with diabetes and can result in severe medical problems for these patients and for society. Negative-pressure wound therapy (NPWT) has been adopted to treat intractable chronic wounds and has been reported to be effective. However, the mechanisms underlying the effects of this treatment have not been elucidated. To assess the vasculogenic effect of NPWT, we evaluated the systemic mobilization of endothelial progenitor cells (EPCs) during NPWT. Twenty-two of 29 consecutive patients who presented at the clinic of Seoul National Universty Hospital between December 2009 and November 2010 who underwent NPWT for diabetic foot infections or skin ulcers were included in this study. Peripheral blood samples were taken before NPWT (pre-NPWT) and 7–14 days after the initiation of NPWT (during-NPWT). Fluorescence-activated cell sorting (FACS) analysis showed that the number of cells in EPC-enriched fractions increased after NPWT, and the numbers of EPC colony forming units (CFUs) significantly increased during NPWT. We believe that NPWT is useful for treating patients with diabetic foot infections and skin ulcers, especially when these conditions are accompanied by peripheral arterial insufficiency. The systemic mobilization of EPCs during NPWT may be a mechanism for healing intractable wounds in diabetic patients with foot infections or skin defects via the formation of increased granulation tissue with numerous small blood vessels.
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Affiliation(s)
- Sang Gyo Seo
- Department of Orthopedic Surgery, Seoul National University College of Medicine, Seoul, Korea
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Kim IS, Cho TH, Lee ZH, Hwang SJ. Bone regeneration by transplantation of human mesenchymal stromal cells in a rabbit mandibular distraction osteogenesis model. Tissue Eng Part A 2013; 19:66-78. [PMID: 23083133 DOI: 10.1089/ten.tea.2011.0696] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Ex vivo expanded mesenchymal stromal cells (MSCs) represent a potential cell population for tissue regeneration strategy. Xenogeneic transplantation using human MSCs (hMSCs) can be an approach to reveal what hMSCs guide in bone regeneration with distinguishable gene expression from a host animal. In this study, we investigated the regenerating effect of hMSCs varying injection time point in a rabbit distraction osteogenesis model. Undifferentiated hMSCs (2×10(6) cells) were injected transcutaneously into the osteotomy site of one side of the mandible 1 day before the onset of distraction (Group 1) or after distraction (Group 2). The contralateral side of the mandible, which was subjected to distraction, but no hMSC injection, was used as the control in each group. hMSCs showed lack of major histocompatibility complex class II expression and suppression of xenogeneic lymphocyte proliferation stimulated by a proinflammatory cytokine. A microcomputed tomography-based evaluation showed a significant increase in new bone volume in the distracted callus in Group 1 compared to the contralateral side. Injection of hMSCs increased the bone mineral density (BMD) of the regenerated bone in both Group 1 and 2, although the former had a higher BMD than the latter. hMSCs of Group 1 subjected to distraction after injection expressed insulin-like growth factor-1 (IGF-1) and fibronectin (FN), while the expression of most osteoblast differentiation-related markers and growth factors was negligible. These results demonstrated that hMSCs exerted immune suppressive behavior in rabbit T cells in vitro, and hMSC transplantation into the distracted callus of a rabbit model provided osteogenic benefits that were more pronounced when the hMSCs were injected just before distraction than at the end of distraction. The beneficial effect of hMSCs might be mediated, partly by the expression of matrix proteins or IGF-1, which are known to favor bone formation.
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Affiliation(s)
- In Sook Kim
- Dental Research Institute, Seoul National University, Seoul, Republic of Korea
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Yellowley C. CXCL12/CXCR4 signaling and other recruitment and homing pathways in fracture repair. BONEKEY REPORTS 2013; 2:300. [PMID: 24422056 DOI: 10.1038/bonekey.2013.34] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Accepted: 02/08/2013] [Indexed: 02/06/2023]
Abstract
Cell recruitment, migration and homing to the fracture site are essential for the inflammatory process, neovascularization, chondrogenesis, osteogenesis and ultimately bone remodeling. Mesenchymal stem cells (MSCs) are required to navigate from local sources such as the periosteum and local bone marrow, and may also be recruited from the circulation and distant bone marrow. While the local recruitment process may involve matrix binding and degradation, systemic recruitment may utilize extravasation, a process used by leukocytes to exit the vasculature. CXCL12 (stromal cell-derived factor-1 (SDF-1)), a member of the CXC family of chemokines, is thought to have an important role in cell migration at the fracture site. However, there are many molecules upregulated in the hematoma and callus that have chemotactic potential not only for inflammatory cells but also for endothelial cells and MSCs. Surprisingly, there is little direct data to support their role in cell homing during bone healing. Current therapeutics for bone regeneration utilize local or systemic stem cell transplantation. More recently, a novel strategy that involves mobilization of large numbers of endogenous stem and progenitor cells from bone marrow into the circulation has been shown to have positive effects on bone healing. A more complete understanding of the molecular mechanisms underlying cell recruitment and homing subsequent to fracture will facilitate the fine-tuning of such strategies for bone.
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Affiliation(s)
- Clare Yellowley
- Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis , Davis, CA, USA
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Zhou B, Wu G, An Y, He X, Teng L. The effect of continuous elastic outside distraction on the expressions of vascular endothelial cell growth factor and microvessel density in female porcine nipple. Aesthetic Plast Surg 2012; 36:723-31. [PMID: 22190139 DOI: 10.1007/s00266-011-9851-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2011] [Accepted: 10/16/2011] [Indexed: 01/10/2023]
Abstract
BACKGROUND We have proposed a method to correct the inverted nipple with good clinical results. The aim of the study presented here is to show the effect of continuous elastic distraction on the expression of vascular endothelial growth factor and microvessel density in the female porcine nipple. This article also explores the probable mechanism correction of inverted nipples. METHODS Four female 3-month-old pigs each with 12 nipples were used. Four nipples of each minipig were used as control with the other eight nipples continuously distracted with prefabricated instruments. The nipples were excised at weeks 2, 4, 8, and 12 after distraction. Immunohistochemical staining was performed to observe the expression of vascular endothelial cell growth factor (VEGF) and CD34 in those tissues. The integral optical density of VEGF-positive cells and microvessel density (MVD) were also counted. RESULTS The volumes of the nipples all increased after traction compared with those of the control group. The diameters and heights of the nipples showed significant changes (P<0.01). In immunohistochemical staining, the expressions of VEGF and CD34 of all distracted groups were positive. The staining intensity of traction groups was moderate and that of the control groups was weakly positive. The integral optical density of VEGF-positive cells and MVD compared with the control group were significantly different (P<0.01), and there was a significant positive correlation in MVD and VEGF. CONCLUSION Continuous elastic distraction can promote the expression of some growth factors in nipples.
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Sun HH, Qu TJ, Zhang XH, Yu Q, Chen FM. Designing biomaterials for in situ periodontal tissue regeneration. Biotechnol Prog 2011; 28:3-20. [PMID: 21913341 DOI: 10.1002/btpr.698] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2011] [Revised: 07/11/2011] [Indexed: 01/25/2023]
Abstract
The regeneration of periodontal tissue poses a significant challenge to biomaterial scientists, tissue engineers and periodontal clinicians. Recent advances in this field have shifted the focus from the attempt to recreate tissue replacements/constructs ex vivo to the development of biofunctionalized biomaterials that incorporate and release regulatory signals in a precise and near-physiological fashion to achieve in situ regeneration. The molecular and physical information coded within the biomaterials define a local biochemical and mechanical niche with complex and dynamic regulation that establishes key interactions with host endogenous cells and, hence, may help to unlock latent regenerative pathways in the body by instructing cell homing and regulating cell proliferation/differentiation. In the future, these innovative principles and biomaterial devices promise to have a profound impact on periodontal reconstructive therapy and are also likely to reconcile the clinical and commercial pressures on other tissue engineering endeavors.
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Affiliation(s)
- Hai-Hua Sun
- Department of Operative Dentistry & Endodontics, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, PR China
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Kuroda R, Matsumoto T, Miwa M, Kawamoto A, Mifune Y, Fukui T, Kawakami Y, Niikura T, Lee SY, Oe K, Shoji T, Kuroda T, Horii M, Yokoyama A, Ono T, Koibuchi Y, Kawamata S, Fukushima M, Kurosaka M, Asahara T. Local transplantation of G-CSF-mobilized CD34(+) cells in a patient with tibial nonunion: a case report. Cell Transplant 2010; 20:1491-6. [PMID: 21176407 DOI: 10.3727/096368910x550189] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Although implantation of crude bone marrow cells has been applied in a small number of patients for fracture healing, transplantation of peripheral blood CD34(+) cells, the hematopoietic/endothelial progenitor cell-enriched population, in patients with fracture has never been reported. Here, we report the first case of tibial nonunion receiving autologous, granulocyte colony stimulating factor mobilized CD34(+) cells accompanied with autologous bone grafting. No serious adverse event occurred, and the novel therapy performed 9 months after the primary operation resulted in bone union 3 months later without any symptoms including pain and gait disturbance.
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Affiliation(s)
- Ryosuke Kuroda
- Department of Orthopedic Surgery, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
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