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Sutthiwanjampa C, Kang SH, Kim MK, Hwa Choi J, Kim HK, Woo SH, Bae TH, Kim WJ, Kang SH, Park H. Tumor necrosis factor-α-treated human adipose-derived stem cells enhance inherent radiation tolerance and alleviate in vivo radiation-induced capsular contracture. J Adv Res 2025; 72:433-449. [PMID: 39019109 DOI: 10.1016/j.jare.2024.07.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 07/10/2024] [Accepted: 07/13/2024] [Indexed: 07/19/2024] Open
Abstract
INTRODUCTION Post-mastectomy radiotherapy plays a crucial role in breast cancer treatment but can lead to an inflammatory response causing soft tissue damage, particularly radiation-induced capsular contracture (RICC), impacting breast reconstruction outcomes. Adipose-derived stem cells (ADSCs), known for their regenerative potential via paracrine capacity, exhibit inherent radiotolerance. The influence of tumor necrosis factor-alpha (TNF-α) on ADSCs has been reported to enhance the paracrine effect of ADSCs, promoting wound healing by modulating inflammatory responses. OBJECTIVE This study investigates the potential of TNF-α-treated human ADSCs (T-hASCs) on silicone implants to alleviate RICC, hypothesizing to enhance suppressive effects on RICC by modulating inflammatory responses in a radiation-exposed environment. METHODS In vitro, T-hASCs were cultured on various surfaces to assess viability after exposure to radiation up to 20 Gy. In vivo, T-hASC and non-TNF-α-treated hASC (C-hASCs)-coated membranes were implanted in mice before radiation exposure, and an evaluation of the RICC mitigation took place 4 and 8 weeks after implantation. In addition, the growth factors released from T-hASCs were assessed. RESULTS In vitro, hASCs displayed significant radiotolerance, maintaining consistent viability after exposure to 10 Gy. TNF-α treatment further enhanced radiation tolerance, as evidenced by significantly higher viability than C-hASCs at 20 Gy. In vivo, T-hASC-coated implants effectively suppressed RICC, reducing capsule thickness. T-hASCs exhibited remarkable modulation of the inflammatory response, suppressing M1 macrophage polarization while enhancing M2 polarization. The elevated secretion of vascular endothelial growth factor from T-hASCs is believed to induce macrophage polarization, potentially reducing RICC. CONCLUSION This study establishes T-hASCs as a promising strategy for ameliorating the adverse effects experienced by breast reconstruction patients after mastectomy and radiation therapy. The observed radiotolerance, anti-fibrotic effects, and immune modulation suggest the possibility of enhancing patient outcomes and quality of life. Further research and clinical trials are warranted for broader clinical uses.
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Affiliation(s)
- Chanutchamon Sutthiwanjampa
- School of Integrative Engineering, Chung-Ang University, 84 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06974, Republic of Korea; College of Medicine, Chung-Ang University, 84 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06974, Republic of Korea
| | - Seung Hyun Kang
- College of Medicine, Chung-Ang University, 84 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06974, Republic of Korea; Department of Plastic and Reconstructive Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06973, Republic of Korea
| | - Mi Kyung Kim
- College of Medicine, Chung-Ang University, 84 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06974, Republic of Korea; Departments of Pathology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06973, Republic of Korea
| | - Jin Hwa Choi
- College of Medicine, Chung-Ang University, 84 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06974, Republic of Korea; Department of Radiation Oncology, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06973, Republic of Korea
| | - Han Koo Kim
- Department of Plastic and Reconstructive Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06973, Republic of Korea
| | - Soo Hyun Woo
- Department of Plastic and Reconstructive Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06973, Republic of Korea
| | - Tae Hui Bae
- Department of Plastic and Reconstructive Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06973, Republic of Korea
| | - Woo Joo Kim
- Department of Plastic Surgery, Chung-Ang University Gwangmyeong Hospital, Chung-Ang University College of Medicine, Gwangmyeong-si, Gyeonggi-do 14353, Republic of Korea
| | - Shin Hyuk Kang
- College of Medicine, Chung-Ang University, 84 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06974, Republic of Korea; Department of Plastic and Reconstructive Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, 102 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06973, Republic of Korea.
| | - Hansoo Park
- School of Integrative Engineering, Chung-Ang University, 84 Heukseok-ro, Heukseok-dong, Dongjak-gu, Seoul 06974, Republic of Korea.
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Chiu A, Rutkowski JM, Zhang Q, Zhao F. Tissue-Engineered Therapeutics for Lymphatic Regeneration: Solutions for Myocardial Infarction and Secondary Lymphedema. Adv Healthc Mater 2025; 14:e2403551. [PMID: 39806804 PMCID: PMC11936459 DOI: 10.1002/adhm.202403551] [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: 09/18/2024] [Revised: 12/12/2024] [Indexed: 01/16/2025]
Abstract
The lymphatic system, which regulates inflammation and fluid homeostasis, is damaged in various diseases including myocardial infarction (MI) and breast-cancer-related lymphedema (BCRL). Mounting evidence suggests that restoring tissue fluid drainage and clearing excess immune cells by regenerating damaged lymphatic vessels can aid in cardiac repair and lymphedema amelioration. Current treatments primarily address symptoms rather than underlying causes due to a lack of regenerative therapies, highlighting the importance of the lymphatic system as a promising novel therapeutic target. Here cutting-edge research on engineered lymphatic tissues, growth factor therapies, and cell-based approaches designed to enhance lymphangiogenesis and restore lymphatic function is explored. Special focus is placed on how therapies with potential for immediate lymphatic reconstruction, originally designed for treating BCRL, can be applied to MI to augment cardiac repair and reduce heart failure risk. The integration of these novel treatments can significantly improve patient outcomes by promoting lymphatic repair, preventing pathological remodeling, and offering new avenues for managing lymphatic-associated diseases.
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Affiliation(s)
- Alvis Chiu
- Department of Biomedical Engineering, College of Engineering, Texas A&M University, 5045 Emerging Technologies Building 3120 TAMU, College Station, TX 77843-3120
| | - Joseph M. Rutkowski
- Department of Medical Physiology, College of Medicine, Texas A&M University, Medical Research and Education Building, 8447 Riverside Pkwy, Bryan, TX 77807-3260
| | - Qixu Zhang
- Department of Plastic Surgery, Division of Surgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030
| | - Feng Zhao
- Department of Biomedical Engineering, College of Engineering, Texas A&M University, 5045 Emerging Technologies Building 3120 TAMU, College Station, TX 77843-3120
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Jørgensen MG, Jensen CH, Hermann AP, Andersen DC, Toyserkani NM, Sheikh SP, Sørensen JA. No Clinical Efficacy of Adipose-Derived Regenerative Cells and Lipotransfer in Breast Cancer-Related Lymphedema: A Double-Blind Placebo-Controlled Phase II Trial. Plast Reconstr Surg 2024; 154:1172-1182. [PMID: 39591365 DOI: 10.1097/prs.0000000000011343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/04/2024]
Abstract
BACKGROUND Breast cancer-related lymphedema (BCRL) is a debilitating sequela affecting up to 1 in 3 breast cancer survivors. Treatments are palliative and do not address the underlying lymphatic injury. Recent preclinical and nonrandomized studies have shown promising results using adipose-derived regenerative cells (ADRCs) and lipotransfer in alleviating BCRL through regeneration of lymphatic tissue. However, no randomized controlled trial has been performed in an attempt to eliminate a placebo effect. METHODS This randomized, double-blind, placebo-controlled trial included patients with no-option, persistent disabling unilateral BCRL. Patients were randomly assigned in a 1:1 ratio to receive either autologous ADRCs (4.20×10 7 ± 1.75×10 7 cells) and 30-cc lipotransfer or placebo (saline) to the axilla. The primary outcome was a change in BCRL volume 1 year after treatment. Secondary outcomes included changes in quality of life, indocyanine green lymphangiography stage, bioimpedance, and safety. RESULTS Eighty patients were included, of whom 39 were allocated to ADRCs and lipotransfer treatment and 41 to placebo treatment. Baseline characteristics were similar in the groups. One year after treatment, no objective improvements were observed in the treatment or placebo groups. In contrast, significant subjective improvements were noted for both the treatment and placebo groups. CONCLUSIONS This trial failed to confirm a benefit of ADRCs and lipotransfer in the treatment of BCRL. These nonconfirmatory results suggest that ADRC and lipotransfer should not be recommended for alleviating BCRL. However, the authors cannot exclude that repeated treatments or higher doses of ADRCs or lipotransfer could yield a clinical effect. CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, I.
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Affiliation(s)
- Mads Gustaf Jørgensen
- From the Departments of Plastic and Reconstructive Surgery
- Open Patient Data Explorative Network (OPEN), Odense University Hospital
- Clinical Institute, University of Southern Denmark
| | | | | | | | | | - Søren Paludan Sheikh
- Clinical Biochemistry and Pharmacology
- Clinical Institute, University of Southern Denmark
| | - Jens Ahm Sørensen
- From the Departments of Plastic and Reconstructive Surgery
- Clinical Institute, University of Southern Denmark
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Wang YC, Shueng PW, Hu CY, Tung FI, Chen MH, Liu TY. Hyaluronic acid-based injectable formulation developed to mitigate metastasis and radiation-induced skin fibrosis in breast cancer treatment. Carbohydr Polym 2024; 336:122136. [PMID: 38670762 DOI: 10.1016/j.carbpol.2024.122136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 04/04/2024] [Accepted: 04/05/2024] [Indexed: 04/28/2024]
Abstract
The standard treatment for early-stage breast cancer involves breast-conserving surgery followed by adjuvant radiotherapy. However, approximately 20 % of patients experience distant metastasis, and adjuvant radiotherapy often leads to radiation-induced skin fibrosis (RISF). In this study, we develop an on-site injectable formulation composed of selenocystamine (SeCA) and hyaluronic acid (HyA), referred to as SeCA cross-linked HyA (SCH) agent, and investigate its potential to mitigate metastasis and prevent RISF associated with breast cancer therapy. SCH agents are synthesized using the nanoprecipitation method to modulate cell-cell tight junctions and tissue inflammation. The toxicity assessments reveal that SCH agents with a higher Se content (Se payload 17.4 μg/mL) are well tolerated by L929 cells compared to SeCA (Se payload 3.2 μg/mL). In vitro, SCH agents significantly enhance cell-cell tight junctions and effectively mitigate migration and invasion of breast cancer cells (4T1). In vivo, SCH agents mitigate distant lung metastasis. Furthermore, in animal models, SCH agents reduce RISF and promote wound repair. These findings highlight the potential of SCH agents as a novel therapeutic formulation for effectively mitigating metastasis and reducing RISF. This holds great promise for improving clinical outcomes in breast cancer patients undergoing adjuvant radiotherapy.
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Affiliation(s)
- Yu-Chi Wang
- Department of Biomedical Engineering, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
| | - Pei-Wei Shueng
- Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan; Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
| | - Chan-Yu Hu
- Department of Biomedical Engineering, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
| | - Fu-I Tung
- Department of Orthopaedics, Yang-Ming Branch, Taipei City Hospital, Taipei 111024, Taiwan; Department of Health and Welfare, College of City Management, University of Taipei, Taipei 111036, Taiwan
| | - Ming-Hong Chen
- Division of Neurosurgery, Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 220216, Taiwan; Department of Electrical Engineering, Yuan Ze University, Taoyuan City 320315, Taiwan
| | - Tse-Ying Liu
- Department of Biomedical Engineering, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
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Arriola-Alvarez I, Jaunarena I, Izeta A, Lafuente H. Progenitor Cell Sources for 3D Bioprinting of Lymphatic Vessels and Potential Clinical Application. Tissue Eng Part A 2024; 30:353-366. [PMID: 37950710 DOI: 10.1089/ten.tea.2023.0204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2023] Open
Abstract
The lymphatic system maintains tissue fluid homeostasis and it is involved in the transport of nutrients and immunosurveillance. It also plays a pivotal role in both pathological and regenerative processes. Lymphatic development in the embryo occurs by polarization and proliferation of lymphatic endothelial cells from the lymph sacs, that is, lymphangiogenesis. Alternatively, lymphvasculogenesis further contributes to the formation of lymphatic vessels. In adult tissues, lymphatic formation rarely occurs under physiological conditions, being restricted to pathological processes. In lymphvasculogenesis, progenitor cells seem to be a source of lymphatic vessels. Indeed, mesenchymal stem cells, adipose stem cells, endothelial progenitor cells, and colony-forming endothelial cells are able to promote lymphatic regeneration by different mechanisms, such as direct differentiation and paracrine effects. In this review, we summarize what is known on the diverse stem/progenitor cell niches available for the lymphatic system, emphasizing the potential that these cells hold for lymphatic tissue engineering through 3D bioprinting and their translation to clinical application.
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Affiliation(s)
- Inazio Arriola-Alvarez
- Tissue Engineering Group, Biogipuzkoa Health Research Institute, Donostia-San Sebastián, Spain
| | - Ibon Jaunarena
- Gynecology Oncology Unit, Donostia University Hospital, Donostia-San Sebastián, Spain
- Obstetrics and Gynaecology Group, Biogipuzkoa Health Research Institute, Donostia-San Sebastián, Spain
- University of the Basque Country (UPV/EHU), Department of Medical Surgical Specialties, Leioa, Spain
| | - Ander Izeta
- Tissue Engineering Group, Biogipuzkoa Health Research Institute, Donostia-San Sebastián, Spain
- Department of Biomedical Engineering and Sciences, Tecnun-University of Navarra, Donostia-San Sebastián, Spain
| | - Héctor Lafuente
- Tissue Engineering Group, Biogipuzkoa Health Research Institute, Donostia-San Sebastián, Spain
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陈 君, 邓 呈. [Research advances on stem cell-based treatments in animal studies and clinical trials of lymphedema]. ZHONGGUO XIU FU CHONG JIAN WAI KE ZA ZHI = ZHONGGUO XIUFU CHONGJIAN WAIKE ZAZHI = CHINESE JOURNAL OF REPARATIVE AND RECONSTRUCTIVE SURGERY 2024; 38:99-106. [PMID: 38225848 PMCID: PMC10796233 DOI: 10.7507/1002-1892.202309045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/16/2023] [Indexed: 01/17/2024]
Abstract
Objective To summarize the progress of the roles and mechanisms of various types of stem cell-based treatments and their combination therapies in both animal studies and clinical trials of lymphedema. Methods The literature on stem cell-based treatments for lymphedema in recent years at home and abroad was extensively reviewed, and the animal studies and clinical trials on different types of stem cells for lymphedema were summarized. Results Various types of stem cells have shown certain effects in animal studies and clinical trials on the treatment of lymphedema, mainly through local differentiation into lymphoid endothelial cells and paracrine cytokines with different functions. Current research focuses on two cell types, adipose derived stem cells and bone marrow mesenchymal stem cells, both of which have their own advantages and disadvantages, mainly reflected in the therapeutic effect of stem cells, the difficulty of obtaining stem cells and the content in vivo. In addition, stem cells can also play a synergistic role in combination with other treatments, such as conservative treatment, surgical intervention, cytokines, biological scaffolds, and so on. However, it is still limited to the basic research stage, and only a small number of studies have completed clinical trials. Conclusion Stem cells have great transformation potential in the treatment of lymphedema, but there is no unified standard in the selection of cell types, the amount of transplanted cells, and the timing of transplantation.
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Affiliation(s)
- 君哲 陈
- 遵义医科大学附属医院烧伤整形外科（贵州遵义 563003）Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi Guizhou, 563003, P. R. China
| | - 呈亮 邓
- 遵义医科大学附属医院烧伤整形外科（贵州遵义 563003）Department of Burns and Plastic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi Guizhou, 563003, P. R. China
- 组织损伤修复与再生医学省部共建协同创新中心（贵州遵义 563003）Collaborative Innovation Center of Tissue Repair and Regenerative Medicine, Zunyi Guizhou, 563003, P. R. China
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Morita Y, Sakata N, Nishimura M, Kawakami R, Shimizu M, Yoshimatsu G, Sawamoto O, Matsumoto S, Wada H, Kodama S. Efficacy of Neonatal Porcine Bone Marrow-Derived Mesenchymal Stem Cell Xenotransplantation for the Therapy of Hind Limb Lymphedema in Mice. Cell Transplant 2024; 33:9636897241260195. [PMID: 38867486 PMCID: PMC11179447 DOI: 10.1177/09636897241260195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 04/22/2024] [Accepted: 05/22/2024] [Indexed: 06/14/2024] Open
Abstract
Lymphedema is an intractable disease with few effective therapeutic options. Autologous mesenchymal stem cell (MSC) transplantation is a promising therapy for this disease. However, its use is limited by the cost and time for preparation. Recently, xenotransplantation of porcine MSCs has emerged as an alternative to autologous MSC transplantation. In this study, we aimed to clarify the usefulness of neonatal porcine bone marrow-derived MSC (NpBM-MSC) xenotransplantation for the treatment of lymphedema. One million NpBM-MSCs were xenotransplanted into the hind limbs of mice with severe lymphedema (MSC transplantation group). The therapeutic effects were assessed by measuring the femoral circumference, the volume of the hind limb, the number and diameter of lymphatic vessels in the hind limb, and lymphatic flow using a near-infrared fluorescence (NIRF) imaging system. We compared the effects using mice with lymphedema that did not undergo NpBM-MSC transplantation (negative control group). The condition of the transplanted NpBM-MSCs was also evaluated histologically. The femoral circumference and volume of the hind limb had been normalized by postoperative day (POD) 14 in the MSC transplantation group, but not in the negative control group (P = 0.041). NIRF imaging revealed that lymphatic flow had recovered in the MSC transplantation group by POD 14, as shown by an increase in luminance in the hind limb. Histological assessment also showed that the xenotransplantation of NpBM-MSC increased the proliferation of lymphatic vessels, but they had been rejected by POD 14. The xenotransplantation of NpBM-MSCs is an effective treatment for lymphedema, and this is mediated through the promotion of lymphangiogenesis.
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Affiliation(s)
- Yuichi Morita
- Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
- Department of Cardiovascular Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Naoaki Sakata
- Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
- Research Institute for Regenerative Medicine, Fukuoka University, Fukuoka, Japan
| | - Masuhiro Nishimura
- Research and Development Center, Otsuka Pharmaceutical Factory, Inc., Naruto, Japan
| | - Ryo Kawakami
- Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
- Research Institute for Regenerative Medicine, Fukuoka University, Fukuoka, Japan
| | - Masayuki Shimizu
- Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
- Department of Cardiovascular Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Gumpei Yoshimatsu
- Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
- Research Institute for Regenerative Medicine, Fukuoka University, Fukuoka, Japan
| | - Osamu Sawamoto
- Research and Development Center, Otsuka Pharmaceutical Factory, Inc., Naruto, Japan
| | - Shinichi Matsumoto
- Research and Development Center, Otsuka Pharmaceutical Factory, Inc., Naruto, Japan
| | - Hideichi Wada
- Department of Cardiovascular Surgery, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Research Institute for Regenerative Medicine, Fukuoka University, Fukuoka, Japan
| | - Shohta Kodama
- Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
- Research Institute for Regenerative Medicine, Fukuoka University, Fukuoka, Japan
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Bucan A, Frendø M, Ngo MT, Sørensen JA, Hölmich LR. Surgical lymphedema models in the mice hindlimb-A systematic review and quality assessment. Microsurgery 2024; 44:e31088. [PMID: 37665032 DOI: 10.1002/micr.31088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 05/30/2023] [Accepted: 06/28/2023] [Indexed: 09/05/2023]
Abstract
BACKGROUND Lymphedema constitutes a major unsolved problem in plastic surgery. To identify novel lymphedema treatments, preclinical studies are vital. The surgical mouse lymphedema model is popular and cost-effective; nonetheless, a synthesis and overview of the literature with evidence-based guidelines is needed. The aim of this review was to perform a systematic review to establish best practice and support future high-quality animal studies exploring lymphedema treatments. METHODS We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching four databases (PubMed, Embase, Web of Science, and Scopus) from inception-September 2022. The Animals in Research Reporting In Vivo Experiments 2.0 (ARRIVE 2.0) guidelines were used to evaluate reporting quality. Studies claiming to surgically induce lymphedema in the hindlimb of mice were included. RESULTS Thirty-seven studies were included. Four main models were used. (1) Irradiation+surgery. (2) A variation of the surgery used by (1) + irradiation. (3) Surgery only (SPDF-model). (4) Surgery only (PLND-model). Remaining studies used other techniques. The most common measurement modality was the caliper. Mean quality coefficient was 0.57. Eighteen studies (49%) successfully induced sustained lymphedema. Combination of methods seemed to yield the best results, with an overrepresentation of irradiation, the removal of two lymph nodes, and the disruption of both the deep and superficial lymph vessels in the 18 studies. CONCLUSION Surgical mouse hindlimb lymphedema models are challenged by two related problems: (1) retaining lymphedema for an extended period, that is, establishing a (chronic) lymphedema model (2) distinguishing lymphedema from post-operative edema. Most studies failed to induce lymphedema and used error-prone measurements. We provide an overview of studies claiming to induce lymphedema and advocate improved research via five evidence-based recommendations to use: (1) a proven lymphedema model; (2) sufficient follow-up time, (3) validated measurement methods; (4) ARRIVE-guidelines; (5) contralateral hindlimb as control.
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Affiliation(s)
- Amar Bucan
- Department of Plastic Surgery, University of Copenhagen, Herlev and Gentofte Hospital, Copenhagen, Denmark
| | - Martin Frendø
- Department of Plastic Surgery, University of Copenhagen, Herlev and Gentofte Hospital, Copenhagen, Denmark
- Copenhagen Academy for Medical Education and Simulation (CAMES), Center for HR & Education, Copenhagen, Denmark
| | - Mikaella Ty Ngo
- Department of Plastic Surgery, University of Copenhagen, Herlev and Gentofte Hospital, Copenhagen, Denmark
| | - Jens Ahm Sørensen
- Research Unit for Plastic Surgery, Odense University Hospital, Odense, Denmark
| | - Lisbet Rosenkrantz Hölmich
- Department of Plastic Surgery, University of Copenhagen, Herlev and Gentofte Hospital, Copenhagen, Denmark
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Wang D, Zhao Y, Zhou Y, Yang S, Xiao X, Feng L. Angiogenesis-An Emerging Role in Organ Fibrosis. Int J Mol Sci 2023; 24:14123. [PMID: 37762426 PMCID: PMC10532049 DOI: 10.3390/ijms241814123] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/02/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
In recent years, the study of lymphangiogenesis and fibrotic diseases has made considerable achievements, and accumulating evidence indicates that lymphangiogenesis plays a key role in the process of fibrosis in various organs. Although the effects of lymphangiogenesis on fibrosis disease have not been conclusively determined due to different disease models and pathological stages of organ fibrosis, its importance in the development of fibrosis is unquestionable. Therefore, we expounded on the characteristics of lymphangiogenesis in fibrotic diseases from the effects of lymphangiogenesis on fibrosis, the source of lymphatic endothelial cells (LECs), the mechanism of fibrosis-related lymphangiogenesis, and the therapeutic effect of intervening lymphangiogenesis on fibrosis. We found that expansion of LECs or lymphatic networks occurs through original endothelial cell budding or macrophage differentiation into LECs, and the vascular endothelial growth factor C (VEGFC)/vascular endothelial growth factor receptor (VEGFR3) pathway is central in fibrosis-related lymphangiogenesis. Lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), as a receptor of LECs, is also involved in the regulation of lymphangiogenesis. Intervention with lymphangiogenesis improves fibrosis to some extent. In the complex organ fibrosis microenvironment, a variety of functional cells, inflammatory factors and chemokines synergistically or antagonistically form the complex network involved in fibrosis-related lymphangiogenesis and regulate the progression of fibrosis disease. Further clarifying the formation of a new fibrosis-related lymphangiogenesis network may potentially provide new strategies for the treatment of fibrosis disease.
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Affiliation(s)
| | | | | | | | | | - Li Feng
- Division of Liver Surgery, Department of General Surgery and Regeneration Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China; (D.W.); (Y.Z.); (Y.Z.); (S.Y.); (X.X.)
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Kang HJ, Moon SY, Kim BK, Myung Y, Lee JH, Jeong JH. Recellularized lymph node scaffolds with human adipose-derived stem cells enhance lymph node regeneration to improve lymphedema. Sci Rep 2023; 13:5397. [PMID: 37012287 PMCID: PMC10070624 DOI: 10.1038/s41598-023-32473-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Accepted: 03/28/2023] [Indexed: 04/05/2023] Open
Abstract
To overcome the limitations of lymphedema treatment, human adipose-derived stem cells (hADSCs) were injected into decellularized lymph nodes to produce a recellularized lymph node-scaffold, and the effect of lymphangiogenesis was investigated in lymphedema animal models. Axillary lymph nodes were harvested from Sprague Dawley rats (7 weeks old, 220-250 g) for decellularization. The decellularized lymph nodes were performed and PKH26-labeled hADSCs (1 × 106/50 µL) were injected in the decellularized lymph node-scaffolds. Forty rats were equally divided into four groups: lymphedema as control group, hADSC group, decellularized lymph node-scaffold group, and recellularized lymph node-scaffold group. The lymphedema model was made by removing inguinal lymph nodes, and hADSCs or scaffolds were transplanted. Histopathological assessments were performed by hematoxylin and eosin and Masson's trichrome staining. Lymphangiogenesis was evaluated by Immunofluorescence staining and western blot. Decellularized lymph nodes showed virtually complete absence of cellular material and maintenance of lymph node architecture. The hADSCs were significantly observed in recellularized lymph node-scaffolds group. The recellularized lymph node-scaffold group was histologically similar to normal lymph nodes. The vascular endothelial growth factor A and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) in immunofluorescence staining were highly expressed in recellularized lymph node-scaffolds group. Also, the expression of LYVE-1 protein significantly increased in recellularized lymph node-scaffold group compared with others. Recellularized lymph node -scaffold had a much better therapeutic effect than stem cells or decellularized lymph node-scaffold alone, and induced stable lymphangiogenesis.
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Affiliation(s)
- Hyo Jin Kang
- Department of Biomedical Laboratory Science, Honam University, Gwangju, 62399, Republic of Korea
| | - Soo Young Moon
- Department of Biomedical Laboratory Science, Honam University, Gwangju, 62399, Republic of Korea
| | - Baek-Kyu Kim
- Department of Plastic and Reconstructive Surgery, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, 13620, Gyeonggi-do, Republic of Korea
| | - Yujin Myung
- Department of Plastic and Reconstructive Surgery, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, 13620, Gyeonggi-do, Republic of Korea
| | - Ju-Hee Lee
- College of Korean Medicine, Dongguk University, Goyang, 10326, Gyeonggi-do, Republic of Korea
| | - Jae Hoon Jeong
- Department of Plastic and Reconstructive Surgery, Seoul National University Bundang Hospital, 82, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam-si, 13620, Gyeonggi-do, Republic of Korea.
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11
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Ruliffson BNK, Whittington CF. Regulating Lymphatic Vasculature in Fibrosis: Understanding the Biology to Improve the Modeling. Adv Biol (Weinh) 2023; 7:e2200158. [PMID: 36792967 DOI: 10.1002/adbi.202200158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 12/19/2022] [Indexed: 02/17/2023]
Abstract
Fibrosis occurs in many chronic diseases with lymphatic vascular insufficiency (e.g., kidney disease, tumors, and lymphedema). New lymphatic capillary growth can be triggered by fibrosis-related tissue stiffening and soluble factors, but questions remain for how related biomechanical, biophysical, and biochemical cues affect lymphatic vascular growth and function. The current preclinical standard for studying lymphatics is animal modeling, but in vitro and in vivo outcomes often do not align. In vitro models can also be limited in their ability to separate vascular growth and function as individual outcomes, and fibrosis is not traditionally included in model design. Tissue engineering provides an opportunity to address in vitro limitations and mimic microenvironmental features that impact lymphatic vasculature. This review discusses fibrosis-related lymphatic vascular growth and function in disease and the current state of in vitro lymphatic vascular models while highlighting relevant knowledge gaps. Additional insights into the future of in vitro lymphatic vascular models demonstrate how prioritizing fibrosis alongside lymphatics will help capture the complexity and dynamics of lymphatics in disease. Overall, this review aims to emphasize that an advanced understanding of lymphatics within a fibrotic disease-enabled through more accurate preclinical modeling-will significantly impact therapeutic development toward restoring lymphatic vessel growth and function in patients.
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Affiliation(s)
- Brian N K Ruliffson
- Department of Biomedical Engineering, Worcester Polytechnic Institute, 100 Institute Rd., Worcester, MA, 01609, USA
| | - Catherine F Whittington
- Department of Biomedical Engineering, Worcester Polytechnic Institute, 100 Institute Rd., Worcester, MA, 01609, USA
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12
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Chiu A, Jia W, Sun Y, Goldman J, Zhao F. Fibroblast-Generated Extracellular Matrix Guides Anastomosis during Wound Healing in an Engineered Lymphatic Skin Flap. Bioengineering (Basel) 2023; 10:bioengineering10020149. [PMID: 36829643 PMCID: PMC9952048 DOI: 10.3390/bioengineering10020149] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/04/2023] [Accepted: 01/17/2023] [Indexed: 01/25/2023] Open
Abstract
A healthy lymphatic system is required to return excess interstitial fluid back to the venous circulation. However, up to 49% of breast cancer survivors eventually develop breast cancer-related lymphedema due to lymphatic injuries from lymph node dissections or biopsies performed to treat cancer. While early-stage lymphedema can be ameliorated by manual lymph drainage, no cure exists for late-stage lymphedema when lymph vessels become completely dysfunctional. A viable late-stage treatment is the autotransplantation of functional lymphatic vessels. Here we report on a novel engineered lymphatic flap that may eventually replace the skin flaps used in vascularized lymph vessel transfers. The engineered flap mimics the lymphatic and dermal compartments of the skin by guiding multi-layered tissue organization of mesenchymal stem cells and lymphatic endothelial cells with an aligned decellularized fibroblast matrix. The construct was tested in a novel bilayered wound healing model and implanted into athymic nude rats. The in vitro model demonstrated capillary invasion into the wound gaps and deposition of extracellular matrix fibers, which may guide anastomosis and vascular integration of the graft during wound healing. The construct successfully anastomosed in vivo, forming chimeric vessels of human and rat cells. Overall, our flap replacement has high potential for treating lymphedema.
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Affiliation(s)
- Alvis Chiu
- Stem Cell and Tissue Engineering Lab, Department of Biomedical Engineering, College of Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Wenkai Jia
- Stem Cell and Tissue Engineering Lab, Department of Biomedical Engineering, College of Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Yumeng Sun
- Stem Cell and Tissue Engineering Lab, Department of Biomedical Engineering, College of Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Jeremy Goldman
- Vascular Materials Lab, Department of Biomedical Engineering, College of Engineering, Michigan Technological University, Houghton, MI 49931, USA
| | - Feng Zhao
- Stem Cell and Tissue Engineering Lab, Department of Biomedical Engineering, College of Engineering, Texas A&M University, College Station, TX 77843, USA
- Correspondence:
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13
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Wang YC, Meng WT, Zhang HF, Zhu J, Wang QL, Mou FF, Guo HD. Lymphangiogenesis, a potential treatment target for myocardial injury. Microvasc Res 2023; 145:104442. [PMID: 36206847 DOI: 10.1016/j.mvr.2022.104442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 07/26/2022] [Accepted: 09/29/2022] [Indexed: 11/07/2022]
Abstract
The lymphatic vascular system is crucial for the regulation of tissue fluid homeostasis, lipid metabolism, and immune function. Cardiac injury quickly leads to myocardial edema, cardiac lymphatic dysfunction, which ultimately results in myocardial fluid imbalance and cardiac dysfunction. Therefore, lymphangiogenesis-targeted therapy may improve the recovery of myocardial function post cardiac ischemia as observed in myocardial infarction (MI). Indeed, a promising strategy for the clinical treatment of MI relies on vascular endothelial growth factor-C (VEGF-C)-targeted therapy, which promotes lymphangiogenesis. However, much effort is needed to identify the mechanisms of lymphatic transport in response to heart disease. This article reviews regulatory factors of lymphangiogenesis, and discusses the effects of lymphangiogenesis on cardiac function after cardiac injury and its regulatory mechanisms. The involvement of stem cells on lymphangiogenesis was also discussed as stem cells could differentiate into lymphatic endothelial cells (LECs) and stimulate phenotype of LECs.
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Affiliation(s)
- Ya-Chao Wang
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wan-Ting Meng
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Hai-Feng Zhang
- Department of Human Anatomy, Xuzhou Medical University, Xuzhou 221004, China
| | - Jing Zhu
- Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qiang-Li Wang
- School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Fang-Fang Mou
- Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Hai-Dong Guo
- Academy of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Department of Anatomy, School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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14
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The Impact of Stem/Progenitor Cells on Lymphangiogenesis in Vascular Disease. Cells 2022; 11:cells11244056. [PMID: 36552820 PMCID: PMC9776475 DOI: 10.3390/cells11244056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 12/03/2022] [Accepted: 12/12/2022] [Indexed: 12/16/2022] Open
Abstract
Lymphatic vessels, as the main tube network of fluid drainage and leukocyte transfer, are responsible for the maintenance of homeostasis and pathological repairment. Recently, by using genetic lineage tracing and single-cell RNA sequencing techniques, significant cognitive progress has been made about the impact of stem/progenitor cells during lymphangiogenesis. In the embryonic stage, the lymphatic network is primarily formed through self-proliferation and polarized-sprouting from the lymph sacs. However, the assembly of lymphatic stem/progenitor cells also guarantees the sustained growth of lymphvasculogenesis to obtain the entire function. In addition, there are abundant sources of stem/progenitor cells in postnatal tissues, including circulating progenitors, mesenchymal stem cells, and adipose tissue stem cells, which can directly differentiate into lymphatic endothelial cells and participate in lymphangiogenesis. Specifically, recent reports indicated a novel function of lymphangiogenesis in transplant arteriosclerosis and atherosclerosis. In the present review, we summarized the latest evidence about the diversity and incorporation of stem/progenitor cells in lymphatic vasculature during both the embryonic and postnatal stages, with emphasis on the impact of lymphangiogenesis in the development of vascular diseases to provide a rational guidance for future research.
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15
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Nurlaila I, Roh K, Yeom CH, Kang H, Lee S. Acquired lymphedema: Molecular contributors and future directions for developing intervention strategies. Front Pharmacol 2022; 13:873650. [PMID: 36386144 PMCID: PMC9640931 DOI: 10.3389/fphar.2022.873650] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Accepted: 10/13/2022] [Indexed: 08/05/2023] Open
Abstract
Lymphedema is a debilitating chronic disease that mostly develops as an adverse reaction to cancer treatment modalities such as chemotherapy, surgery, and radiotherapy. Lymphedema also appears to be a deteriorating consequence of roundworm infections, as best represented by filariasis. According to its origin, lymphedema is classified as primary lymphedema and acquired lymphedema. The latter is an acquired condition that, hitherto, received a considerably low attention owing to the less number of fatal cases been reported. Notably, despite the low mortality rate in lymphedema, it has been widely reported to reduce the disease-free survival and thus the quality of life of affected patients. Hence, in this review, we focused on acquired lymphedema and orchestration of molecular interplays associated with either stimulation or inhibition of lymphedema development that were, in vast majority, clearly depicted in animal models with their specific and distinct technical approaches. We also discussed some recent progress made in phytochemical-based anti-lymphedema intervention strategies and the specific mechanisms underlying their anti-lymphedema properties. This review is crucial to understand not only the comprehensive aspects of the disease but also the future directions of the intervention strategies that can address the quality of life of affected patients rather than alleviating apparent symptoms only.
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Affiliation(s)
- Ika Nurlaila
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, South Korea
- Department of Vaccine and Drugs, The National Research and Innovation Agency, Jakarta, Indonesia
| | - Kangsan Roh
- Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
- Division of Cardiology and Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
| | | | - Hee Kang
- Humanitas College, Kyung Hee University, Yongin, South Korea
| | - Sukchan Lee
- Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, South Korea
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16
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Tang H, He Y, Liang Z, Li J, Dong Z, Liao Y. The therapeutic effect of adipose-derived stem cells on soft tissue injury after radiotherapy and their value for breast reconstruction. Stem Cell Res Ther 2022; 13:493. [PMID: 36195925 PMCID: PMC9531407 DOI: 10.1186/s13287-022-02952-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 06/08/2022] [Indexed: 12/24/2022] Open
Abstract
Background Postmastectomy radiotherapy is considered to be a necessary treatment in the therapy of breast cancer, while it will cause soft tissue damage and complications, which are closely related to the success rate and effectiveness of breast reconstruction. After radiotherapy, cutaneous tissue becomes thin and brittle, and its compliance decreases. Component fat grafting and adipose-derived stem cell therapy are considered to have great potential in treating radiation damage and improving skin compliance after radiotherapy. Main body In this paper, the basic types and pathological mechanisms of skin and soft tissue damage to breast skin caused by radiation therapy are described. The 2015–2021 studies related to stem cell therapy in PubMed were also reviewed. Studies suggest that adipose-derived stem cells exert their biological effects mainly through cargoes carried in extracellular vesicles and soluble secreted factors. Compared to traditional fat graft breast reconstruction, ADSC therapy amplifies the effects of stem cells in it. In order to obtain a more purposeful therapeutic effect, proper stem cell pretreatment may achieve more ideal and safe results. Conclusion Recent research works about ADSCs and other MSCs mainly focus on curative effects in the acute phase of radiation injury, and there is little research about treatment of chronic phase complications. The efficacy of stem cell therapy on alleviating skin fibrosis and its underlying mechanism require further research.
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Affiliation(s)
- Haojing Tang
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Yufei He
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Zhuokai Liang
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Jian Li
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China
| | - Ziqing Dong
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China.
| | - Yunjun Liao
- The Department of Plastic and Cosmetic Surgery, Nanfang Hospital, Southern Medical University, 1838 Guangzhou North Road, Guangzhou, 510515, Guangdong, China.
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17
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Hsu JF, Yu RP, Stanton EW, Wang J, Wong AK. Current Advancements in Animal Models of Postsurgical Lymphedema: A Systematic Review. Adv Wound Care (New Rochelle) 2022; 11:399-418. [PMID: 34128396 PMCID: PMC9142133 DOI: 10.1089/wound.2021.0033] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
Significance: Secondary lymphedema is a debilitating disease caused by lymphatic dysfunction characterized by chronic swelling, dysregulated inflammation, disfigurement, and compromised wound healing. Since there is no effective cure, animal model systems that support basic science research into the mechanisms of secondary lymphedema are critical to advancing the field. Recent Advances: Over the last decade, lymphatic research has led to the improvement of existing animal lymphedema models and the establishment of new models. Although an ideal model does not exist, it is important to consider the strengths and limitations of currently available options. In a systematic review adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we present recent developments in the field of animal lymphedema models and provide a concise comparison of ease, cost, reliability, and clinical translatability. Critical Issues: The incidence of secondary lymphedema is increasing, and there is no gold standard of treatment or cure for secondary lymphedema. Future Directions: As we iterate and create animal models that more closely characterize human lymphedema, we can achieve a deeper understanding of the pathophysiology and potentially develop effective therapeutics for patients.
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Affiliation(s)
- Jerry F. Hsu
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA.,Division of Plastic Surgery, City of Hope National Medical Center, Duarte, California, USA.,Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Roy P. Yu
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA
| | - Eloise W. Stanton
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA
| | - Jin Wang
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA.,Division of Plastic Surgery, City of Hope National Medical Center, Duarte, California, USA
| | - Alex K. Wong
- Division of Plastic and Reconstructive Surgery, Keck School of Medicine of USC, Los Angeles, California, USA.,Division of Plastic Surgery, City of Hope National Medical Center, Duarte, California, USA.,Correspondence: Division of Plastic Surgery, City of Hope National Medical Center, 1500 E. Duarte Road, Pavillion 2216, Duarte, CA 91010, USA.
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18
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Ogino R, Yokooji T, Hayashida M, Suda S, Yamakawa S, Hayashida K. Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema. Int J Mol Sci 2022; 23:ijms23147614. [PMID: 35886961 PMCID: PMC9322118 DOI: 10.3390/ijms23147614] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/05/2022] [Accepted: 07/07/2022] [Indexed: 02/04/2023] Open
Abstract
Secondary lymphedema is a common complication of lymph node dissection or radiation therapy for cancer treatment. Conventional therapies such as compression sleeve therapy, complete decongestive physiotherapy, and surgical therapies decrease edema; however, they are not curative because they cannot modulate the pathophysiology of lymphedema. Recent advances reveal that the activation and accumulation of CD4+ T cells are key in the development of lymphedema. Based on this pathophysiology, the efficacy of pharmacotherapy (tacrolimus, anti-IL-4/IL-13 antibody, or fingolimod) and cell-based therapy for lymphedema has been demonstrated in animal models and pilot studies. In addition, mesenchymal stem/stromal cells (MSCs) have attracted attention as candidates for cell-based lymphedema therapy because they improve symptoms and decrease edema volume in the long term with no serious adverse effects in pilot studies. Furthermore, MSC transplantation promotes functional lymphatic regeneration and improves the microenvironment in animal models. In this review, we focus on inflammatory cells involved in the pathogenesis of lymphedema and discuss the efficacy and challenges of pharmacotherapy and cell-based therapies for lymphedema.
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Affiliation(s)
- Ryohei Ogino
- Department of Frontier Science for Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (R.O.); (T.Y.)
| | - Tomoharu Yokooji
- Department of Frontier Science for Pharmacotherapy, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan; (R.O.); (T.Y.)
| | - Maiko Hayashida
- Department of Psychiatry, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan;
| | - Shota Suda
- Division of Plastic and Reconstructive Surgery, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan; (S.S.); (S.Y.)
| | - Sho Yamakawa
- Division of Plastic and Reconstructive Surgery, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan; (S.S.); (S.Y.)
| | - Kenji Hayashida
- Division of Plastic and Reconstructive Surgery, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan; (S.S.); (S.Y.)
- Correspondence: ; Tel.: +81-853-20-2210
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19
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Role of Transcriptional and Epigenetic Regulation in Lymphatic Endothelial Cell Development. Cells 2022; 11:cells11101692. [PMID: 35626729 PMCID: PMC9139870 DOI: 10.3390/cells11101692] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/13/2022] [Accepted: 05/17/2022] [Indexed: 12/04/2022] Open
Abstract
The lymphatic system is critical for maintaining the homeostasis of lipids and interstitial fluid and regulating the immune cell development and functions. Developmental anomaly-induced lymphatic dysfunction is associated with various pathological conditions, including lymphedema, inflammation, and cancer. Most lymphatic endothelial cells (LECs) are derived from a subset of endothelial cells in the cardinal vein. However, recent studies have reported that the developmental origin of LECs is heterogeneous. Multiple regulatory mechanisms, including those mediated by signaling pathways, transcription factors, and epigenetic pathways, are involved in lymphatic development and functions. Recent studies have demonstrated that the epigenetic regulation of transcription is critical for embryonic LEC development and functions. In addition to the chromatin structures, epigenetic modifications may modulate transcriptional signatures during the development or differentiation of LECs. Therefore, the understanding of the epigenetic mechanisms involved in the development and function of the lymphatic system can aid in the management of various congenital or acquired lymphatic disorders. Future studies must determine the role of other epigenetic factors and changes in mammalian lymphatic development and function. Here, the recent findings on key factors involved in the development of the lymphatic system and their epigenetic regulation, LEC origins from different organs, and lymphatic diseases are reviewed.
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20
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Yang Y, Li XB, Li Y, Li TX, Li P, Deng GM, Guo Q, Zhou X, Chen XH. Extracellular Vesicles Derived From Hypoxia-Conditioned Adipose-Derived Mesenchymal Stem Cells Enhance Lymphangiogenesis. Cell Transplant 2022; 31:9636897221107536. [PMID: 35861534 PMCID: PMC9310282 DOI: 10.1177/09636897221107536] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Extracellular vesicles from adipose-derived mesenchymal stem cells (ADSCs) play an important role in lymphangiogenesis; however, the underlying mechanisms are not fully understood. In this study, we aimed to investigate the function of extracellular vesicles secreted by hypoxia-conditioned ADSCs in lymphangiogenesis and explore the potential molecular mechanisms. Extracellular vesicles were extracted from ADSCs cultured under hypoxia or normoxia conditions. The uptake of extracellular vesicles by lymphatic endothelial cells (LECs) was detected by immunofluorescence staining. The effects of extracellular vesicles on the viability, migration, and tube formation of LECs were determined by CCK-8 assay, migration assay, and tube formation assay, respectively. Molecules and pathway involved in lymphangiogenesis mediated by ADSC-derived extracellular vesicles were analyzed by luciferase reporter assay, qRT-polymerase chain reaction (PCR), and Western blot. Hypoxia ADSC-derived extracellular vesicles (H-ADSC/evs) significantly enhanced the proliferation, migration, and tube formation of LECs. Hypoxia decreased the expression of miR-129 in ADSC-derived extracellular vesicles. Overexpression of miR-129 counteracted the promoting effect of H-ADSC/evs on lymphangiogenesis. In addition, decreased exosomal miR-129 expression resulted in upregulation of HMGB1 in LECs, which led to AKT activation and lymphangiogenesis enhancement. Our data reveal that extracellular vesicles derived from hypoxia-conditioned ADSCs induce lymphangiogenesis, and this effect is mediated by miR-129/HMGB1/AKT signaling. Our findings imply that hypoxia ADSC-isolated extracellular vesicles may represent as a valuable target for the treatment of diseases associated with lymphatic remodeling.
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Affiliation(s)
- Yi Yang
- Department of Microsurgery, Trauma and Hand Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xu-Bo Li
- Department of Microsurgery, Trauma and Hand Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yu Li
- Department of Microsurgery, Trauma and Hand Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Tian-Xiao Li
- Department of Pharmacy, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China
| | - Ping Li
- Department of Microsurgery, Trauma and Hand Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Guang-Mao Deng
- Department of Orthopedic, Huiya Hospital, The First Affiliated Hospital of Sun Yat-sen University, Huizhou, China
| | - Qiang Guo
- Department of Orthopedic, Huiya Hospital, The First Affiliated Hospital of Sun Yat-sen University, Huizhou, China
| | - Xiang Zhou
- Department of Microsurgery, Trauma and Hand Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Xiao-Hu Chen
- Department of Orthopedic, Huiya Hospital, The First Affiliated Hospital of Sun Yat-sen University, Huizhou, China
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21
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Frueh FS, Gassert L, Scheuer C, Müller A, Fries P, Boewe AS, Ampofo E, Rübe CE, Menger MD, Laschke MW. Adipose tissue-derived microvascular fragments promote lymphangiogenesis in a murine lymphedema model. J Tissue Eng 2022; 13:20417314221109957. [PMID: 35923176 PMCID: PMC9340320 DOI: 10.1177/20417314221109957] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 06/12/2022] [Indexed: 12/22/2022] Open
Abstract
Chronic lymphedema after cancer treatment is common and there is still no cure for this disease. We herein investigated the lymphangiogenic capacity of adipose tissue-derived microvascular fragments (MVF), which contain stem cells and lymphatic vessel fragments. Secondary lymphedema was induced in the hindlimbs of C57BL/6J mice. Green fluorescence protein (GFP)+ MVF were isolated from transgenic C57BL/6Tg (CAG-EGFP)1Osb/J mice, suspended in collagen hydrogel, and injected in the lymphadenectomy defect of wild-type animals. This crossover model allowed the detection of MVF-derived blood and lymphatic vessels after transplantation. The MVF group was compared with animals receiving collagen hydrogel only or a sham intervention. Lymphangiogenic effects were analyzed using volumetry, magnetic resonance (MR) lymphography, histology, and immunohistochemistry. MVF injection resulted in reduced hindlimb volumes when compared to non-treated controls. MR lymphography revealed lymphatic regeneration with reduced dermal backflow after MVF treatment. Finally, MVF transplantation promoted popliteal angiogenesis and lymphangiogenesis associated with a significantly increased microvessel and lymphatic vessel density. These findings indicate that MVF transplantation represents a promising approach to induce therapeutic lymphangiogenesis.
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Affiliation(s)
- Florian S Frueh
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Laura Gassert
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Claudia Scheuer
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Andreas Müller
- Clinic of Diagnostic and Interventional Radiology, Saarland University Medical Center, Homburg/Saar, Germany
| | - Peter Fries
- Clinic of Diagnostic and Interventional Radiology, Saarland University Medical Center, Homburg/Saar, Germany
| | - Anne S Boewe
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Emmanuel Ampofo
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Claudia E Rübe
- Department of Radiotherapy and Radiation Oncology, Saarland University Medical Centre, Homburg/Saar, Germany
| | - Michael D Menger
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
| | - Matthias W Laschke
- Institute for Clinical and Experimental Surgery, Saarland University, Homburg/Saar, Germany
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22
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Li ZJ, Wang LQ, Li YZ, Wang CY, Huang JZ, Yu NZ, Long X. Application of adipose-derived stem cells in treating fibrosis. World J Stem Cells 2021; 13:1747-1761. [PMID: 34909121 PMCID: PMC8641015 DOI: 10.4252/wjsc.v13.i11.1747] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/18/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Fibrosis is the hyperactivation of fibroblasts that results in excessive accumulation of extracellular matrix, which is involved in numerous pathological changes and diseases. Adipose-derived stem cells (ASCs) are promising seed cells for regenerative medicine due to their bountiful source, low immunogenicity and lack of ethical issues. Their anti-fibrosis, immunomodulation, angiogenesis and other therapeutic effects have made them suitable for treating fibrosis-related diseases. Here, we review the literature on ASCs treating fibrosis, elaborate and discuss their mechanisms of action, changes in disease environment, ways to enhance therapeutic effects, as well as current preclinical and clinical studies, in order to provide a general picture of ASCs treating fibrotic diseases.
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Affiliation(s)
- Zhu-Jun Li
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Li-Quan Wang
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Yun-Zhu Li
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Chen-Yu Wang
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Jiu-Zuo Huang
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Nan-Ze Yu
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Xiao Long
- Department of Plastic and Reconstructive Surgery, Peking Union Medical College Hospital of Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
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23
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Lafuente H, Jaunarena I, Ansuategui E, Lekuona A, Izeta A. Cell therapy as a treatment of secondary lymphedema: a systematic review and meta-analysis. Stem Cell Res Ther 2021; 12:578. [PMID: 34801084 PMCID: PMC8605543 DOI: 10.1186/s13287-021-02632-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/16/2021] [Indexed: 12/09/2022] Open
Abstract
Background Lymphedema, the accumulation of interstitial fluid caused by poor lymphatic drainage, is a progressive and permanent disease with no curative treatment. Several studies have evaluated cell-based therapies in secondary lymphedema, but no meta-analysis has been performed to assess their efficacy. Methods We conducted a systematic review and meta-analysis of all available preclinical and clinical studies, with assessment of their quality and risk of bias. Results A total of 20 articles using diverse cell types were selected for analysis, including six clinical trials and 14 pre-clinical studies in three species. The meta-analysis showed a positive effect of cell-based therapies on relevant disease outcomes (quantification of edema, density of lymphatic capillaries, evaluation of the lymphatic flow, and tissue fibrosis). No significant publication bias was observed. Conclusion Cell-based therapies have the potential to improve secondary lymphedema. The underlying mechanisms remain unclear. Due to relevant heterogeneity between studies, further randomized controlled and blinded studies are required to substantiate the use of these novel therapies in clinical practice.
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Affiliation(s)
- Hector Lafuente
- Tissue Engineering Group, Biodonostia Health Research Institute, 20014, San Sebastián, Spain
| | - Ibon Jaunarena
- Gynecology Oncology Unit, Donostia University Hospital, 20014, San Sebastián, Spain.,Obstetrics and Gynaecology Group, Biodonostia Health Research Institute, 20014, San Sebastián, Spain
| | - Eukene Ansuategui
- Clinical Epidemiology Group, Biodonostia Health Research Institute, 20014, San Sebastián, Spain
| | - Arantza Lekuona
- Gynecology Oncology Unit, Donostia University Hospital, 20014, San Sebastián, Spain.,Obstetrics and Gynaecology Group, Biodonostia Health Research Institute, 20014, San Sebastián, Spain
| | - Ander Izeta
- Tissue Engineering Group, Biodonostia Health Research Institute, 20014, San Sebastián, Spain. .,School of Engineering, Tecnun-University of Navarra, 20009, San Sebastián, Spain.
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24
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Chen HL, Su YC, Chen HC, Su JH, Wu CY, Wang SW, Lin IP, Chen CY, Lee CH. Heteronemin Suppresses Lymphangiogenesis through ARF-1 and MMP-9/VE-Cadherin/Vimentin. Biomedicines 2021; 9:1109. [PMID: 34572295 PMCID: PMC8471334 DOI: 10.3390/biomedicines9091109] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/17/2021] [Accepted: 08/26/2021] [Indexed: 02/07/2023] Open
Abstract
Lymphatic metastasis is a biological procedure associated with the pathogenesis of several diseases, especially in tumor metastasis. Therefore, regulation of lymphangiogenesis has become a promising strategy for cancer therapy. In this study, we aimed to investigate the anti-lymphangiogenic effect of heteronemin (SP-1) isolated from the sponge Hyrtios sp. in vitro and in vivo. Human lymphatic endothelial cells (LECs) were utilized to evaluate the anti-lymphangiogenic effect of SP-1 in vitro. Molecular docking, western blotting, flow-cytometry, MTT and ELISA were performed to investigate the mechanism of action. For in vivo approaches, the transgenic (fli1:EGFP; gata1:DsRed) zebrafish and mouse ear sponges were used. Molecular docking studies showed that SP-1 is a potent vascular endothelial growth factor receptor 3 (VEGFR-3)-binding compound. Treatment of LEC with SP-1 reduced the phosphorylation of VEGFR-3. SP-1 suppressed the development of the thoracic duct in zebrafish and mouse lymphangiogenesis ear sponges in vivo. Mechanistically, SP-1 induced the cell cycle arrest of LECs in the G0/G1 phase and reduced the downstream of VEGFR-3, such as phosphorylated MEK/ERK and NF-κB. In addition, SP-1 inhibited LECs' tubulogenesis and migration through the ARF-1 and MMP-9/VE-cadherin/vimentin. Overall, anti-lymphangiogenic properties of SP-1 occur by downregulating the VEGFR-3 cascade, ARF-1 and MMP-9/VE-cadherin/vimentin. Collectively, these results proposed that SP-1 might be a potential candidate for the treatment of lymphangiogenesis-associated diseases.
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Affiliation(s)
- Hsien-Lin Chen
- Division of General Surgery, Department of Surgery, Chi-Mei Medical Center, Liouying, Tainan 73657, Taiwan;
| | - Yu-Chieh Su
- Department of Medicine, School of Medicine, I-Shou University, Kaohsiung 840203, Taiwan;
- Division of Hematology-Oncology, Department of Internal Medicine, E-Da Hospital, Kaohsiung 824410, Taiwan
| | - Huang-Chi Chen
- Department of Internal Medicine, Kaohsiung Municipal Siaogang Hospital, Kaohsiung 81267, Taiwan;
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
| | - Jui-Hsin Su
- National Museum of Marine Biology & Aquarium, Institute of Marine Biotechnology, National Dong Hwa University, Pingtung 94401, Taiwan;
| | - Chang-Yi Wu
- Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
- Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 804201, Taiwan
| | - Shih-Wei Wang
- Department of Medicine, Mackay Medical College, New Taipei City 252005, Taiwan;
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - In-Pin Lin
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Chung-Yi Chen
- Department of Nutrition and Health Science, School of Medical and Health Sciences, Fooyin University, Kaohsiung 83102, Taiwan;
| | - Chien-Hsing Lee
- Department of Pharmacology, School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 80708, Taiwan
- Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
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25
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Zhang N, Hu L, Liu J, Yang W, Li Y, Pan J. Wnt Signaling Regulates the Lymphatic Endothelial Transdifferentiation of Adipose-Derived Stromal Cells In Vitro. Cell Reprogram 2021; 23:117-126. [PMID: 33780637 DOI: 10.1089/cell.2020.0058] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Lymphedema is a chronic, progressive disease that causes pain as well as heavy economic burdens to patients. Reconstruction of the impaired lymphatic system is the key to treat lymphedema. Currently, there is no cure, but mesenchymal stromal cells show promising potential for lymphatic endothelial regeneration. Adipose-derived stromal cells (ADSCs) have been proved to support lymphangiogenesis both in vivo and in vitro. However, the mechanism in vascular endothelial growth factor C-induced (VEGF-C-induced) lymphatic endothelial transdifferentiation of ADSCs remains unknown. In this study, we show a novel link between the Wingless and int-1 (Wnt) pathway and the lymphatic endothelial differentiation process. We used LiCl to activate Wnt and DKK-1 to inhibit Wnt. Compared with the Wnt inhibition group and the control groups, the Wnt activation group produced more lymphatic endothelial cell (LEC)-related mRNA and proteins. Besides, Wnt-activated ADSCs formed longer tubes in two-dimensional culture and promoted the growth of lymphatic vessels in a three-dimensional transwell ADSC-LEC co-culture system. Our results demonstrated that activation of Wnt during the lymphatic endothelial transdifferentiation of ADSCs would enhance the efficacy of VEGF-C treatment. We anticipate our assay to expand our knowledge of Wnt in cell transdifferentiation and lay a foundation for future efforts to explore a novel and effective ADSC-based therapy for lymphedema.
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Affiliation(s)
- Nian Zhang
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Liru Hu
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jiyuan Liu
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Wenbin Yang
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Ye Li
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
| | - Jian Pan
- State Key Laboratory of Oral Diseases, Department of Oral and Maxillofacial Surgery, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
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26
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Sex Hormones in Lymphedema. Cancers (Basel) 2021; 13:cancers13030530. [PMID: 33573286 PMCID: PMC7866787 DOI: 10.3390/cancers13030530] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/21/2021] [Accepted: 01/27/2021] [Indexed: 01/15/2023] Open
Abstract
Simple Summary Lymphedema is a life-long disease that affects a large number of patients treated for breast-, gynecological-, and urologic cancers in Western countries. Given that hormone levels are strongly modified in these conditions, and that patients widely undergo through hormone therapy, it is tempting to speculate that hormones might be key regulators in the maintenance of lymphedema. Despite an obvious prevalence for women, the role of sex hormones and gender has been poorly investigated in this pathology. This review aims to decipher how sex hormones interact with lymphatic vessels and whether hormone therapy could participate in lymphedema development. Abstract Lymphedema is a disorder of the lymphatic vascular system characterized by impaired lymphatic return resulting in swelling of the extremities and accumulation of undrained interstitial fluid/lymph that results in fibrosis and adipose tissue deposition in the limb. Whereas it is clearly established that primary lymphedema is sex-linked with an average ratio of one male for three females, the role of female hormones, in particular estrogens, has been poorly explored. In addition, secondary lymphedema in Western countries affects mainly women who developed the pathology after breast cancer and undergo through hormone therapy up to five years after cancer surgery. Although lymphadenectomy is identified as a trigger factor, the effect of co-morbidities associated to lymphedema remains elusive, in particular, estrogen receptor antagonists or aromatase inhibitors. In addition, the role of sex hormones and gender has been poorly investigated in the etiology of the pathology. Therefore, this review aims to recapitulate the effect of sex hormones on the physiology of the lymphatic system and to investigate whetherhormone therapy could promote a lymphatic dysfunction leading to lymphedema.
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