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Hirose T, Hotta K, Otsuka R, Seino KI. Mechanism and regulation of the complement activity in kidney xenotransplantation. Transplant Rev (Orlando) 2025; 39:100931. [PMID: 40233672 DOI: 10.1016/j.trre.2025.100931] [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: 10/15/2024] [Revised: 04/05/2025] [Accepted: 04/06/2025] [Indexed: 04/17/2025]
Abstract
Xenotransplantation is emerging as one of several potential solutions for addressing organ donor shortages, with significant progress bringing it closer to clinical application. However, challenges remain, particularly concerning complement system dysregulation caused by species differences, as well as xenoantigens and coagulopathy. Complement regulatory proteins expressed on endothelial cells of donor xenografts are less compatible with complement components in recipients. These difficulties contribute to hyperacute rejection, characterized by antibody-mediated complement activation that destroys the graft within 24 h. Moreover, because molecules are incompatible across different species, ischemia-reperfusion injury or infection can easily elicit complement activity via all three pathways, resulting in xenograft loss via complement-mediated vascular injury. Complement activity also stimulate innate and adaptive immune cells. To address this issue, genetic modifications in donor pigs and the development of novel medicines have been tested in preclinical models with promising results. Pigs modified to express human complement-regulating molecules such as CD46, CD55, and CD59 have shown longer kidney xenograft survivals over years in preclinical models with nonhuman primates, paving the way for clinical trials. Anti-complement component agents such as C1 esterase and C5 inhibitors have also been shown to increase xenograft survivals. This review examines the role of the complement system in kidney xenotransplantation, emphasizing new research and clinical trial advancements.
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Affiliation(s)
- Takayuki Hirose
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan.
| | - Kiyohiko Hotta
- Department of Urology, Hokkaido University Hospital, Sapporo, Japan
| | - Ryo Otsuka
- Massachusetts General Hospital, Department of Surgery, Harvard Medical School, Boston, MA 02114, USA
| | - Ken-Ichiro Seino
- Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Hokkaido, Japan
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Kim YH, Cidonio G, Kanczler JM, Oreffo ROC, Dawson JI. Human bone tissue-derived ECM hydrogels: Controlling physicochemical, biochemical, and biological properties through processing parameters. Bioact Mater 2025; 43:114-128. [PMID: 39376928 PMCID: PMC11456876 DOI: 10.1016/j.bioactmat.2024.09.007] [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: 11/06/2023] [Revised: 08/21/2024] [Accepted: 09/04/2024] [Indexed: 10/09/2024] Open
Abstract
Decellularized tissues offer significant potential as biological materials for tissue regeneration given their ability to preserve the complex compositions and architecture of the native extracellular matrix (ECM). However, the evaluation and derivation of decellularized matrices from human bone tissue remains largely unexplored. We examined how the physiochemical and biological properties of ECM hydrogels derived from human bone ECM could be controlled by manipulating bone powder size (45-250 μm, 250-1000 μm, and 1000-2000 μm) and ECM composition through modulation of enzyme digestion time (3-5-7 days). A reduction in material bone powder size and an increase in ECM digestion time produced enhanced protein concentrations in the ECM hydrogels, accompanied by the presence of a diverse array of proteins and improved gelation strength. Human bone marrow-derived stromal cells (HBMSCs) cultured on ECM hydrogels from 45 to 250 μm bone powder, over 7 days, demonstrated enhanced osteogenic differentiation compared to hydrogels derived from larger bone powders and collagen gels confirming the potential of the hydrogels as biologically active materials for bone regeneration. Digestion time and bone powder size modulation enabled the generation of hydrogels with enhanced release of ECM proteins and appropriate gelation and rheological properties, offering new opportunities for application in bone repair.
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Affiliation(s)
- Yang-Hee Kim
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, SO16 6YD, United Kingdom
| | - Gianluca Cidonio
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, SO16 6YD, United Kingdom
- Department of Mechanical and Aerospace Engineering (DIMA), Sapienza University of Rome, Via Eudossiana 18, 00184, Rome, Italy
- Center for Life Nano- and Neuro-Science (CLN2S), Istituto Italiano di Tecnologia, Viale Regina Elena 291, 00161, Rome, Italy
| | - Janos M. Kanczler
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, SO16 6YD, United Kingdom
| | - Richard OC. Oreffo
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, SO16 6YD, United Kingdom
| | - Jonathan I. Dawson
- Bone and Joint Research Group, Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, SO16 6YD, United Kingdom
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Ma S, Qi R, Han S, Li Z, Zhang X, Wang G, Liu K, Xu T, Zhang Y, Han D, Zhang J, Wei D, Fan X, Pan D, Jia Y, Li J, Wang Z, Zhang X, Yang Z, Tao K, Yang X, Dou K, Qin W. Plasma exchange and intravenous immunoglobulin prolonged the survival of a porcine kidney xenograft in a sensitized, deceased human recipient. Chin Med J (Engl) 2024:00029330-990000000-01272. [PMID: 39420636 DOI: 10.1097/cm9.0000000000003338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND The primary limitation to kidney transplantation is organ shortage. Recent progress in gene editing and immunosuppressive regimens has made xenotransplantation with porcine organs a possibility. However, evidence in pig-to-human xenotransplantation remains scarce, and antibody-mediated rejection (AMR) is a major obstacle to clinical applications of xenotransplantation. METHODS We conducted a kidney xenotransplantation in a deceased human recipient using a porcine kidney with five gene edits (5GE) on March 25th, 2024 at Xijing Hospital, China. Clinical-grade immunosuppressive regimens were employed, and the observation period lasted 22 days. We collected and analyzed the xenograft function, ultrasound findings, sequential protocol biopsies, and immune surveillance of the recipient during the observation. RESULTS The combination of 5GE in the porcine kidney and clinical-grade immunosuppressive regimens prevented hyperacute rejection. The xenograft kidney underwent delayed graft function in the first week, but urine output increased later and the single xenograft kidney maintained electrolyte and pH homeostasis from postoperative day (POD) 12 to 19. We observed AMR at 24 h post-transplantation, due to the presence of pre-existing anti-porcine antibodies and cytotoxicity before transplantation; this AMR persisted throughout the observation period. Plasma exchange and intravenous immunoglobulin treatment mitigated the AMR. We observed activation of latent porcine cytomegalovirus toward the end of the study, which might have contributed to coagulation disorder in the recipient. CONCLUSIONS 5GE and clinical-grade immunosuppressive regimens were sufficient to prevent hyperacute rejection during pig-to-human kidney xenotransplantation. Pre-existing anti-porcine antibodies predisposed the xenograft to AMR. Plasma exchange and intravenous immunoglobulin were safe and effective in the treatment of AMR after kidney xenotransplantation.
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Affiliation(s)
- Shuaijun Ma
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Ruochen Qi
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Shichao Han
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Zhengxuan Li
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Xiaoyan Zhang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Guohui Wang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Kepu Liu
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Tong Xu
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Yang Zhang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Donghui Han
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Jingliang Zhang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Di Wei
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Xiaozheng Fan
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Dengke Pan
- Clonorgan Co., Ltd., Chengdu, Sichuan 610041, China
| | - Yanyan Jia
- Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Jing Li
- Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Zhe Wang
- Department of Pathology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Xuan Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Zhaoxu Yang
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Kaishan Tao
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Xiaojian Yang
- Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
| | - Weijun Qin
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710032, China
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Guo Z, Yin M, Sun C, Xu G, Wang T, Jia Z, Zhang Z, Zhu C, Zheng D, Wang L, Huang S, Liu D, Zhang Y, Xie R, Gao N, Zhan L, He S, Zhu Y, Li Y, Nashan B, Andrea S, Xu J, Zhao Q, He X. Liver protects neuron viability and electrocortical activity in post-cardiac arrest brain injury. EMBO Mol Med 2024; 16:2322-2348. [PMID: 39300235 PMCID: PMC11479250 DOI: 10.1038/s44321-024-00140-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 07/18/2024] [Accepted: 08/14/2024] [Indexed: 09/22/2024] Open
Abstract
Brain injury is the leading cause of mortality among patients who survive cardiac arrest (CA). Clinical studies have shown that the presence of post-CA hypoxic hepatitis or pre-CA liver disease is associated with increased mortality and inferior neurological recovery. In our in vivo global cerebral ischemia model, we observed a larger infarct area, elevated tissue injury scores, and increased intravascular CD45+ cell adhesion in reperfused brains with simultaneous hepatic ischemia than in those without it. In the ex vivo brain normothermic machine perfusion (NMP) model, we demonstrated that addition of a functioning liver to the brain NMP circuit significantly reduced post-CA brain injury, increased neuronal viability, and improved electrocortical activity. Furthermore, significant alterations were observed in both the transcriptome and metabolome in the presence or absence of hepatic ischemia. Our study highlights the crucial role of the liver in the pathogenesis of post-CA brain injury.
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Affiliation(s)
- Zhiyong Guo
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China.
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China.
| | - Meixian Yin
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
- Department of Anatomy and Neurobiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Chengjun Sun
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
- Department of Organ Transplantation, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Guixing Xu
- Department of Neurosurgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tielong Wang
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Zehua Jia
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Zhiheng Zhang
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Caihui Zhu
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Donghua Zheng
- Intensive Care Unit, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Linhe Wang
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Shanzhou Huang
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Di Liu
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Yixi Zhang
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Rongxing Xie
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Ningxin Gao
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Liqiang Zhan
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Shujiao He
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Yifan Zhu
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Yuexin Li
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China
- NHC Key Laboratory of Assisted Circulation (Sun Yat-sen University), Guangzhou, China
| | - Björn Nashan
- Organ Transplant Center, The First Affiliated Hospital of the University of Science and Technology of China, Hefei, China
| | - Schlegel Andrea
- General and Liver Transplant Surgery Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Jin Xu
- State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China
| | - Qiang Zhao
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China.
| | - Xiaoshun He
- Guangdong Provincial International Cooperation Base of Science and Technology, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Organ Medicine, Guangzhou, China.
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Tector M, Tector AJ. Reducing Early Graft Loss in Xenotransplantation With Histocompatibility Testing. Transplantation 2024; 108:1687-1688. [PMID: 38578706 PMCID: PMC11378261 DOI: 10.1097/tp.0000000000005020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2024]
Affiliation(s)
| | - A Joseph Tector
- Department of Surgery, University of Miami School of Medicine, Miami, FL
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Thom J, Roters N, Schuemann S, Andrée B, Buettner FFR, Hilfiker A, Goecke T, Ramm R. Reduction in Xenogeneic Epitopes on Porcine Endothelial Cells by Periodate Oxidation. Biomedicines 2024; 12:1470. [PMID: 39062043 PMCID: PMC11275244 DOI: 10.3390/biomedicines12071470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 06/28/2024] [Accepted: 06/29/2024] [Indexed: 07/28/2024] Open
Abstract
BACKGROUND Patterns of humoral immune responses represent a major hurdle in terms of pig-to-human xenotransplantation approaches. The best-known xenogeneic glycan antigens present in pigs are the αGal (Galili antigen) and the non-human sialic acid Neu5Gc. As there are further differences between porcine and human cellular surface glycosylation, a much broader range of glycan epitopes with xeno-reactive relevance can be anticipated. Therefore, we set out to chemically modify porcine cellular surface glycans in a global approach by applying sodium periodate (NaIO4) oxidation. METHODS Porcine endothelial cells were exposed to oxidation with 1 to 5 mM NaIO4 for different time periods at 37 °C or 4 °C and under static or dynamic conditions. The impact on cellular survival was determined by applying live/dead assays. Oxidation of αGal-epitopes was assessed by fluorescence microscopy-based quantification of isolectin-B4 (IL-B4) staining. Overall immunogenicity of porcine cells was determined by human serum antibody binding. RESULTS Treatment of porcine endothelial cells and tissues with NaIO4 led to reduced binding of the αGal-specific IL-B4 and/or human serum antibodies. NaIO4 was revealed to be cytotoxic when performed at elevated temperatures and for a prolonged time. However, by applying 2 mM NaIO4 for 60 min at 4 °C, a high extent of cellular viability and a relevant reduction in detectable αGal epitope were observed. No differences were detected irrespectively on whether the cells were oxidized under static or flow conditions. CONCLUSIONS Glycan epitopes on living cells can be oxidized with NaIO4 while maintaining their viability. Accordingly, this strategy holds promise to prevent immune reactions mediated by preformed anti-glycan antibodies.
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Affiliation(s)
- Jonas Thom
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, 30625 Hannover, Germany
| | - Nathalie Roters
- Lower Saxony Centre for Biomedical Engineering, Implant Research and Development, 30625 Hannover, Germany (T.G.)
| | - Slavica Schuemann
- Lower Saxony Centre for Biomedical Engineering, Implant Research and Development, 30625 Hannover, Germany (T.G.)
- Department of Cardiac-, Thoracic-, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany
| | - Birgit Andrée
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, 30625 Hannover, Germany
- Department of Cardiac-, Thoracic-, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany
| | - Falk F. R. Buettner
- Institute of Clinical Biochemistry, Hannover Medical School, 30625 Hannover, Germany
- Proteomics, Institute of Theoretical Medicine, Faculty of Medicine, University of Augsburg, 86159 Augsburg, Germany
| | - Andres Hilfiker
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, 30625 Hannover, Germany
- Lower Saxony Centre for Biomedical Engineering, Implant Research and Development, 30625 Hannover, Germany (T.G.)
| | - Tobias Goecke
- Lower Saxony Centre for Biomedical Engineering, Implant Research and Development, 30625 Hannover, Germany (T.G.)
- Department of Cardiac-, Thoracic-, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany
- Biomedical Research in End Stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), 30625 Hannover, Germany
| | - Robert Ramm
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, 30625 Hannover, Germany
- Lower Saxony Centre for Biomedical Engineering, Implant Research and Development, 30625 Hannover, Germany (T.G.)
- Department of Cardiac-, Thoracic-, Transplantation and Vascular Surgery, Hannover Medical School, 30625 Hannover, Germany
- Biomedical Research in End Stage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL), 30625 Hannover, Germany
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Qi R, Ma S, Han S, Wang G, Zhang X, Liu K, Sun Y, Gong X, Yu M, Zhang X, Yang X, Dou K, Qin W. Intensive Surveillance of Porcine-Rhesus Kidney Xenotransplant Using Different Ultrasound Techniques. Xenotransplantation 2024; 31:e12873. [PMID: 38961605 DOI: 10.1111/xen.12873] [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: 01/02/2024] [Revised: 05/05/2024] [Accepted: 06/06/2024] [Indexed: 07/05/2024]
Abstract
BACKGROUND Significant progress has been made in kidney xenotransplantation in the past few years, and this field is accelerating towards clinical translation. Therefore, surveillance of the xenograft with appropriate tools is of great importance. Ultrasonography has been widely used in kidney allotransplantation and served as an economical and non-invasive method to monitor the allograft. However, questions remain whether the ultrasonographic criteria established for human kidney allograft could also be applied in xenotransplantation. METHODS In the current study, we established a porcine-rhesus life sustaining kidney xenotransplantation model. The xenograft underwent intensive surveillance using gray-scale, colorful Doppler ultrasound as well as 2D shear wave elastography. The kidney growth, blood perfusion, and cortical stiffness were measured twice a day. These parameters were compared with the clinical data including urine output, chemistry, and pathological findings. RESULTS The observation continued for 16 days after transplantation. Decline of urine output and elevated serum creatinine were observed on POD9 and biopsy proven antibody-mediated rejection was seen on the same day. The xenograft underwent substantial growth, with the long axis length increased by 32% and the volume increased by threefold at the end of observation. The resistive index of the xenograft arteries elevated in response to rejection, together with impaired cortical perfusion, while the peak systolic velocity (PSV) was not compromised. The cortical stiffness also increased along with rejection. CONCLUSION In summary, the ultrasound findings of kidney xenograft shared similarities with those in allograft but possessed some unique features. A modified criteria needs to be established for further application of ultrasound in kidney xenotransplantation.
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Affiliation(s)
- Ruochen Qi
- Department of Urology, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
| | - Shuaijun Ma
- Department of Urology, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
| | - Shichao Han
- Department of Urology, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
| | - Guohui Wang
- Department of Urology, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xiaoyan Zhang
- Department of Urology, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
| | - Kepu Liu
- Department of Urology, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
| | - Yuanyuan Sun
- Department of Ultrasound, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xue Gong
- Department of Ultrasound, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
| | - Ming Yu
- Department of Ultrasound, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xuan Zhang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
| | - Xiaojian Yang
- Department of Urology, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
| | - Weijun Qin
- Department of Urology, Xi-Jing Hospital, Fourth Military Medical University, Xi'an, China
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8
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Ladowski JM, Tector M, Martens G, Wang ZY, Burlak C, Reyes L, Estrada J, Adams A, Tector AJ. Late graft failure of pig-to-rhesus renal xenografts has features of glomerulopathy and recipients have anti-swine leukocyte antigen class I and class II antibodies. Xenotransplantation 2024; 31:e12862. [PMID: 38761019 PMCID: PMC11104517 DOI: 10.1111/xen.12862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 03/12/2024] [Accepted: 04/30/2024] [Indexed: 05/20/2024]
Abstract
Prolonged survival in preclinical renal xenotransplantation demonstrates that early antibody mediated rejection (AMR) can be overcome. It is now critical to evaluate and understand the pathobiology of late graft failure and devise new means to improve post xenograft outcomes. In renal allotransplantation the most common cause of late renal graft failure is transplant glomerulopathy-largely due to anti-donor MHC antibodies, particularly anti-HLA DQ antibodies. We evaluated the pig renal xenograft pathology of four long-surviving (>300 days) rhesus monkeys. We also evaluated the terminal serum for the presence of anti-SLA class I and specifically anti-SLA DQ antibodies. All four recipients had transplant glomerulopathy and expressed anti-SLA DQ antibodies. In one recipient tested for anti-SLA I antibodies, the recipient had antibodies specifically reacting with two of three SLA I alleles tested. These results suggest that similar to allotransplantation, anti-MHC antibodies, particularly anti-SLA DQ, may be a barrier to improved long-term xenograft outcomes.
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Affiliation(s)
| | | | - Gregory Martens
- Department of Surgery, Washington University School of Medicine, St. Louis MO
| | - Zheng Yu Wang
- Department of Surgery, University of Miami School of Medicine, Miami, FL
| | - Chris Burlak
- Department of Surgery, University of Miami School of Medicine, Miami, FL
| | - Luz Reyes
- Department of Surgery, University of Miami School of Medicine, Miami, FL
| | - Jose Estrada
- Department of Surgery, University of Miami School of Medicine, Miami, FL
| | - Andrew Adams
- Department of Surgery, University of Minnesota School of Medicine, Minneapolis, MN
| | - A. Joseph Tector
- Department of Surgery, University of Miami School of Medicine, Miami, FL
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9
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Zhang X, Wang H, Xie Q, Zhang Y, Yang Y, Yuan M, Cui Y, Song SY, Lv J, Wang Y. Advancing kidney xenotransplantation with anesthesia and surgery - bridging preclinical and clinical frontiers challenges and prospects. Front Immunol 2024; 15:1386382. [PMID: 38585270 PMCID: PMC10998442 DOI: 10.3389/fimmu.2024.1386382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 03/13/2024] [Indexed: 04/09/2024] Open
Abstract
Xenotransplantation is emerging as a vital solution to the critical shortage of organs available for transplantation, significantly propelled by advancements in genetic engineering and the development of sophisticated immunosuppressive treatments. Specifically, the transplantation of kidneys from genetically engineered pigs into human patients has made significant progress, offering a potential clinical solution to the shortage of human kidney supply. Recent trials involving the transplantation of these modified porcine kidneys into deceased human bodies have underscored the practicality of this approach, advancing the field towards potential clinical applications. However, numerous challenges remain, especially in the domains of identifying suitable donor-recipient matches and formulating effective immunosuppressive protocols crucial for transplant success. Critical to advancing xenotransplantation into clinical settings are the nuanced considerations of anesthesia and surgical practices required for these complex procedures. The precise genetic modification of porcine kidneys marks a significant leap in addressing the biological and immunological hurdles that have traditionally challenged xenotransplantation. Yet, the success of these transplants hinges on the process of meticulously matching these organs with human recipients, which demands thorough understanding of immunological compatibility, the risk of organ rejection, and the prevention of zoonotic disease transmission. In parallel, the development and optimization of immunosuppressive protocols are imperative to mitigate rejection risks while minimizing side effects, necessitating innovative approaches in both pharmacology and clinical practices. Furthermore, the post-operative care of recipients, encompassing vigilant monitoring for signs of organ rejection, infectious disease surveillance, and psychological support, is crucial for ensuring post-transplant life quality. This comprehensive care highlights the importance of a multidisciplinary approach involving transplant surgeons, anesthesiologists, immunologists, infectiologists and psychiatrists. The integration of anesthesia and surgical expertise is particularly vital, ensuring the best possible outcomes of those patients undergoing these novel transplants, through safe procedural practices. As xenotransplantation moving closer to clinical reality, establishing consensus guidelines on various aspects, including donor-recipient selection, immunosuppression, as well as surgical and anesthetic management of these transplants, is essential. Addressing these challenges through rigorous research and collective collaboration will be the key, not only to navigate the ethical, medical, and logistical complexities of introducing kidney xenotransplantation into mainstream clinical practice, but also itself marks a new era in organ transplantation.
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Affiliation(s)
- Xiaojian Zhang
- Central of Reproductive Medicine, Department of Obstetrics and Gynecology, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Hailian Wang
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
| | - Qin Xie
- Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Yang Zhang
- Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Standford, CA, United States
| | - Yixin Yang
- The First Clinical Medical College of Norman Bethune University of Medical Sciences, Jilin, China
| | - Man Yuan
- Eye Center, Renmin Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China
| | - Yuqi Cui
- Department of Geriatrics, Donald W. Reynolds Institute on Aging, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Si-Yuan Song
- Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
| | - Jianzhen Lv
- School of Pharmacy, Guangxi University of Chinese Medicine, Nanning, China
| | - Yi Wang
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
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10
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Schmalkuche K, Schwinzer R, Wenzel N, Valdivia E, Petersen B, Blasczyk R, Figueiredo C. Downregulation of Swine Leukocyte Antigen Expression Decreases the Strength of Xenogeneic Immune Responses towards Renal Proximal Tubular Epithelial Cells. Int J Mol Sci 2023; 24:12711. [PMID: 37628892 PMCID: PMC10454945 DOI: 10.3390/ijms241612711] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/03/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Xenotransplantation reemerged as a promising alternative to conventional transplantation enlarging the available organ pool. However, success of xenotransplantation depends on the design and selection of specific genetic modifications and on the development of robust assays allowing for a precise assessment of tissue-specific immune responses. Nevertheless, cell-based assays are often compromised by low proliferative capacity of primary cells. Proximal tubular epithelial cells (PTECs) play a crucial role in kidney function. Here, we generated immortalized PTECs (imPTECs) by overexpression of simian virus 40 T large antigen. ImPTECs not only showed typical morphology and phenotype, but, in contrast to primary PTECs, they maintained steady cell cycling rates and functionality. Furthermore, swine leukocyte antigen (SLA) class I and class II transcript levels were reduced by up to 85% after transduction with lentiviral vectors encoding for short hairpin RNAs targeting β2-microglobulin and the class II transactivator. This contributed to reducing xenogeneic T-cell cytotoxicity (p < 0.01) and decreasing secretion of pro-inflammatory cytokines such as IL-6 and IFN-γ. This study showed the feasibility of generating highly proliferative PTECs and the development of tissue-specific immunomonitoring assays. Silencing SLA expression on PTECs was demonstrated to be an effective strategy to prevent xenogeneic cellular immune responses and may strongly support graft survival after xenotransplantation.
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Affiliation(s)
- Katharina Schmalkuche
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
- Transregional Collaborative Research Centre 127, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
| | - Reinhard Schwinzer
- Transregional Collaborative Research Centre 127, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
- Transplantation Laboratory, Clinic for General, Visceral and Transplantation-Surgery, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
| | - Nadine Wenzel
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
| | - Emilio Valdivia
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
| | - Björn Petersen
- Transregional Collaborative Research Centre 127, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
- Institute of Farm Animal Genetics, Höltystr. 10, 31535 Neustadt am Rübenberge, Germany
| | - Rainer Blasczyk
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
| | - Constanca Figueiredo
- Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
- Transregional Collaborative Research Centre 127, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hanover, Germany
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11
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Firl DJ, Lassiter G, Hirose T, Policastro R, D'Attilio A, Markmann JF, Kawai T, Hall KC. Clinical and molecular correlation defines activity of physiological pathways in life-sustaining kidney xenotransplantation. Nat Commun 2023; 14:3022. [PMID: 37311769 PMCID: PMC10264453 DOI: 10.1038/s41467-023-38465-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 05/04/2023] [Indexed: 06/15/2023] Open
Abstract
Porcine kidney xenotransplantation is accelerating towards clinical translation. However, despite the demonstrated ability of porcine kidneys to remove metabolic waste products, questions remain about their ability to faithfully recapitulate renal endocrine functions after transplantation. Here we analyze xenograft growth and function of two kidney dependent endocrine pathways in seventeen cynomolgus macaques after kidney xenotransplantation from gene edited Yucatan minipigs. Xenograft growth, the renin-angiotensinogen aldosterone-system, and the calcium-vitamin D-parathyroid hormone axis are assessed using clinical chemistries data, renin activity and beta-C-terminal-telopeptide assays, kidney graft RNA-sequencing and serial ultrasonography. We demonstrate that xenografts transplanted from minipigs show only modest growth and do not substantially contribute to recipient RAAS pathway activity. However, parathyroid hormone-independent hypercalcemia and hypophosphatemia are observed, suggesting a need for close monitoring and timely intervention during human testing. Further study of these phenotypes is warranted in designing prospective clinical trials.
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Affiliation(s)
- Daniel J Firl
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, USA
- eGenesis Inc, Cambridge, MA, USA
| | - Grace Lassiter
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, USA
| | - Takayuki Hirose
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, USA
| | | | - Ashley D'Attilio
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, USA
| | - James F Markmann
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, USA
| | - Tatsuo Kawai
- Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, USA
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12
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Mubarak M. Transitioning of renal transplant pathology from allograft to xenograft and tissue engineering pathology: Are we prepared? World J Transplant 2023; 13:86-95. [PMID: 36968134 PMCID: PMC10037233 DOI: 10.5500/wjt.v13.i3.86] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 12/21/2022] [Accepted: 01/11/2023] [Indexed: 03/16/2023] Open
Abstract
Currently, the most feasible and widely practiced option for patients with end-stage organ failure is the transplantation of part of or whole organs, either from deceased or living donors. However, organ shortage has posed and is still posing a big challenge in this field. Newer options being explored are xenografts and engineered/bioengineered tissues/organs. Already small steps have been taken in this direction and sooner or later, these will become a norm in this field. However, these developments will pose different challenges for the diagnosis and management of problems as compared with traditional allografts. The approach to pathologic diagnosis of dysfunction in these settings will likely be significantly different. Thus, there is a need to increase awareness and prepare transplant diagnosticians to meet this future challenge in the field of xenotransplantation/ regenerative medicine. This review will focus on the current status of transplant pathology and how it will be changed in the future with the emerging scenario of routine xenotransplantation.
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Affiliation(s)
- Muhammed Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi 74200, Sindh, Pakistan
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13
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Rodger D, Cooper DKC. Kidney xenotransplantation: Future clinical reality or science fiction? Nurs Health Sci 2023; 25:161-170. [PMID: 36335558 PMCID: PMC10124775 DOI: 10.1111/nhs.12994] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 10/10/2022] [Accepted: 11/02/2022] [Indexed: 11/07/2022]
Abstract
There is a global shortage of organs for transplantation and despite many governments making significant changes to their organ donation systems, there are not enough kidneys available to meet the demand. This has led scientists and clinicians to explore alternative means of meeting this organ shortfall. One of the alternatives to human organ transplantation is xenotransplantation, which is the transplantation of organs, tissues, or cells between different species. The resurgence of interest in xenotransplantation and recent scientific breakthroughs suggest that genetically engineered pigs may soon present a realistic alternative as sources of kidneys for clinical transplantation. It is therefore important for healthcare professionals to understand what is involved in xenotransplantation and its future implications for their clinical practices. First, we explore the insufficiency of different organ donation systems to meet the kidney shortage. Second, we provide a background and a summary of the progress made so far in xenotransplantation research. Third, we discuss some of the scientific, technological, ethical, and public health issues associated with xenotransplantation. Finally, we summarize the literature on the attitudes of healthcare professionals toward xenotransplantation.
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Affiliation(s)
- Daniel Rodger
- Institute of Health and Social Care, School of Allied and Community Health, London South Bank University, London, UK
- Department of Psychological Sciences, Birkbeck, University of London, London, UK
| | - David K. C. Cooper
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts, USA
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14
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Tatapudi VS, Griesemer AD. Physiologic considerations of pig-to-human kidney xenotransplantation. Curr Opin Nephrol Hypertens 2023; 32:193-198. [PMID: 36683545 DOI: 10.1097/mnh.0000000000000858] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
PURPOSE OF REVIEW The greatest challenge facing end-stage kidney disease (ESKD) patients is the scarcity of transplantable organs. Advances in genetic engineering that mitigate xenogeneic immune responses have made transplantation across species a potentially viable solution to this unmet need. Preclinical studies and recent reports of pig-to-human decedent renal xenotransplantation signify that clinical trials are on the horizon. Here, we review the physiologic differences between porcine and human kidneys that could impede xenograft survival. Topics addressed include porcine renin and sodium handling, xenograft water handling, calcium, phosphate and acid-base balance, responses to porcine erythropoietin and xenograft growth. RECENT FINDINGS Studies in nonhuman primates (NHPs) have demonstrated that genetically modified pig kidneys can survive for an extended period when transplanted into baboons. In recent studies conducted by our group and others, hyperacute rejection did not occur in pig kidneys lacking the α1,3Gal epitope transplanted into brain-dead human recipients. These experimental trials did not study potential clinical abnormalities arising from idiosyncratic xenograft responses to human physiologic stimuli due to the brief duration of observation this model entails. SUMMARY Progress in biotechnology is heralding an era of xenotransplantation. We highlight the physiologic considerations for xenogeneic grafts to succeed.
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Affiliation(s)
- Vasishta S Tatapudi
- NYU Langone Transplant Institute, NYU Langone Health, New York, New York, USA
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15
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Kasravi M, Ahmadi A, Babajani A, Mazloomnejad R, Hatamnejad MR, Shariatzadeh S, Bahrami S, Niknejad H. Immunogenicity of decellularized extracellular matrix scaffolds: a bottleneck in tissue engineering and regenerative medicine. Biomater Res 2023; 27:10. [PMID: 36759929 PMCID: PMC9912640 DOI: 10.1186/s40824-023-00348-z] [Citation(s) in RCA: 79] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 01/30/2023] [Indexed: 02/11/2023] Open
Abstract
Tissue-engineered decellularized extracellular matrix (ECM) scaffolds hold great potential to address the donor shortage as well as immunologic rejection attributed to cells in conventional tissue/organ transplantation. Decellularization, as the key process in manufacturing ECM scaffolds, removes immunogen cell materials and significantly alleviates the immunogenicity and biocompatibility of derived scaffolds. However, the application of these bioscaffolds still confronts major immunologic challenges. This review discusses the interplay between damage-associated molecular patterns (DAMPs) and antigens as the main inducers of innate and adaptive immunity to aid in manufacturing biocompatible grafts with desirable immunogenicity. It also appraises the impact of various decellularization methodologies (i.e., apoptosis-assisted techniques) on provoking immune responses that participate in rejecting allogenic and xenogeneic decellularized scaffolds. In addition, the key research findings regarding the contribution of ECM alterations, cytotoxicity issues, graft sourcing, and implantation site to the immunogenicity of decellularized tissues/organs are comprehensively considered. Finally, it discusses practical solutions to overcome immunogenicity, including antigen masking by crosslinking, sterilization optimization, and antigen removal techniques such as selective antigen removal and sequential antigen solubilization.
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Affiliation(s)
- Mohammadreza Kasravi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151, Iran
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Armin Ahmadi
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151, Iran
| | - Amirhesam Babajani
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151, Iran
| | - Radman Mazloomnejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151, Iran
| | - Mohammad Reza Hatamnejad
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Siavash Shariatzadeh
- Department of Surgery, University of California Los Angeles, Los Angeles, California, USA
| | - Soheyl Bahrami
- Ludwig Boltzmann Institute for Experimental and Clinical Traumatology in AUVA Research Center, Vienna, Austria
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, 1985711151, Iran.
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16
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Negri A, Wilson L. Future Systems of Xenotransplantation: Melding Historical and Bioethical Methodology. Cell Transplant 2023; 32:9636897231170510. [PMID: 37254850 PMCID: PMC10233605 DOI: 10.1177/09636897231170510] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 03/22/2023] [Accepted: 04/03/2023] [Indexed: 06/01/2023] Open
Abstract
The future of xenotransplantation is promising. However, the scientific process behind xenotransplantation, shown through the methodology of history and bioethics, involves stakeholders beyond the laboratory. We present three short vignettes, the history of a 20th-century pioneer in solid organ transplantation, the xenoheart received by David Bennett, and a global system of illegal organ procurement, to highlight the complexity of biomedical practice. Current solid organ transplantation systems are seemingly unsustainable and ineffective in satisfying a growing global demand for organs. Despite the shortcomings of current systems, we argue that the discourse surrounding xenotransplantation science is insufficient to construct a long-lasting and equitable replacement for solid organ transplantation. Xenotransplantation is more than a surgical technique, an interdisciplinary health concern, or a biomedical technology-it is deeply dependent on a series of cultural, historical, and social factors. Incorporating a greater variety of perspectives and disciplines into ongoing discussions of xenotransplantation science, while potentially frustrating in the short term, will act to maximize its potential as a paradigm-shifting science.
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Affiliation(s)
- Adam Negri
- History of Medicine, University of Minnesota,
Minneapolis, MN, USA
| | - Lauren Wilson
- Philosophy, University of Minnesota,
Minneapolis, MN, USA
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17
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Bayliss G. Practical ethical concerns in allocation of pig kidneys to humans. Clin Kidney J 2022; 15:2161-2168. [PMID: 36381360 PMCID: PMC9664566 DOI: 10.1093/ckj/sfac125] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Indexed: 01/04/2024] Open
Abstract
The fundamental ethical question of whether pig organs should be transplanted into humans has been settled, as recent surgeries demonstrating proof of concept demonstrate. Other issues need to be considered and reconciled before xenotransplantation of pig kidneys becomes a solution to the organ shortage for people waiting for a kidney transplant or as a viable alternative to the deceased donor or living donor human kidneys. Human trials will be needed beyond brain-dead individuals to show that xenotransplantation is safe from immunologic and infectious standpoints. Transplant centers will need to show that xenotransplantation provides a long-term benefit to recipients and is financially viable. If trials are successful and receive regulatory approval, pig xenotransplants may become another option for people waiting for a kidney. Before patients are discharged with a functioning xenograft, practical issues with ethical implications remain.
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Affiliation(s)
- George Bayliss
- Alpert Medical School, Brown University, Providence, RI, USA
- Rhode Island Hospital Division Organ Transplantation, Providence, RI, USA
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18
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Meng Q, Wu W, Zhang W, Yuan J, Yang L, Zhang X, Tao K. IL-18BP Improves Early Graft Function and Survival in Lewis-Brown Norway Rat Orthotopic Liver Transplantation Model. Biomolecules 2022; 12:biom12121801. [PMID: 36551229 PMCID: PMC9775331 DOI: 10.3390/biom12121801] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/28/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022] Open
Abstract
Interleukin-18 (IL-18) can effectively activate natural killer (NK) cells and induce large concentrations of interferon-γ (IFN-γ). In healthy humans, IL-18 binding protein (IL-18BP) can inhibit the binding of IL-18 to IL-18R and counteract the biological action of IL-18 due to its high concentration and high affinity, thus preventing the production of IFN-γ and inhibiting NK-cell activation. Through previous studies and the phenomena observed by our group in pig-non-human primates (NHPs) liver transplantation experiments, we proposed that the imbalance in IL-18/IL-18BP expression upon transplantation encourages the activation, proliferation, and cytotoxic effects of NK cells, ultimately causing acute vascular rejection of the graft. In this research, we used Lewis-Brown Norway rat orthotopic liver transplantation (OLTx) as a model of acute vascular rejection. AAV8-Il18bp viral vectors as gene delivery vehicles were constructed for gene therapy to overexpress IL-18BP and alleviate NK-cell rejection of the graft after transplantation. The results showed that livers overexpressing IL-18BP had reduced damage and could function longer after transplantation, effectively improving the survival time of the recipients.
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Affiliation(s)
- Qiang Meng
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Weikang Wu
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Wenjie Zhang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an 710032, China
- Chinese Education Ministry’s Key Laboratory of Western Resources and Modern Biotechnology, Key Laboratory of Biotechnology Shaanxi Province, College of Life Sciences, Northwest University, Xi’an 710032, China
| | - Juzheng Yuan
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Long Yang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an 710032, China
| | - Xuan Zhang
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an 710032, China
- Correspondence: (X.Z.); (K.T.)
| | - Kaishan Tao
- Department of Hepatobiliary Surgery, Xi-Jing Hospital, Fourth Military Medical University, Xi’an 710032, China
- Correspondence: (X.Z.); (K.T.)
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19
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Lu TY, Xu XL, Du XG, Wei JH, Yu JN, Deng SL, Qin C. Advances in Innate Immunity to Overcome Immune Rejection during Xenotransplantation. Cells 2022; 11:cells11233865. [PMID: 36497122 PMCID: PMC9735653 DOI: 10.3390/cells11233865] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 11/26/2022] [Accepted: 11/28/2022] [Indexed: 12/03/2022] Open
Abstract
Transplantation is an effective approach for treating end-stage organ failure. There has been a long-standing interest in xenotransplantation as a means of increasing the number of available organs. In the past decade, there has been tremendous progress in xenotransplantation accelerated by the development of rapid gene-editing tools and immunosuppressive therapy. Recently, the heart and kidney from pigs were transplanted into the recipients, which suggests that xenotransplantation has entered a new era. The genetic discrepancy and molecular incompatibility between pigs and primates results in barriers to xenotransplantation. An increasing body of evidence suggests that innate immune responses play an important role in all aspects of the xenogeneic rejection. Simultaneously, the role of important cellular components like macrophages, natural killer (NK) cells, and neutrophils, suggests that the innate immune response in the xenogeneic rejection should not be underestimated. Here, we summarize the current knowledge about the innate immune system in xenotransplantation and highlight the key issues for future investigations. A better understanding of the innate immune responses in xenotransplantation may help to control the xenograft rejection and design optimal combination therapies.
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Affiliation(s)
- Tian-Yu Lu
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and Innovation of animal model, Beijing 100021, China
| | - Xue-Ling Xu
- National Engineering Laboratory of Animal Breeding, College of Animal Science and Technology, China Agricultural University, Beijing 100193, China
| | - Xu-Guang Du
- State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Jin-Hua Wei
- Cardiovascular Surgery Department, Center of Laboratory Medicine, National Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China
| | - Jia-Nan Yu
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and Innovation of animal model, Beijing 100021, China
| | - Shou-Long Deng
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and Innovation of animal model, Beijing 100021, China
- Correspondence: (S.-L.D.); (C.Q.)
| | - Chuan Qin
- NHC Key Laboratory of Human Disease Comparative Medicine, Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, National Human Diseases Animal Model Resource Center, Beijing Engineering Research Center for Experimental Animal Models of Human Critical Diseases, International Center for Technology and Innovation of animal model, Beijing 100021, China
- Changping National Laboratory (CPNL), Beijing 102206, China
- Correspondence: (S.-L.D.); (C.Q.)
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20
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Groth T, Stegmayr BG, Ash SR, Kuchinka J, Wieringa FP, Fissell WH, Roy S. Wearable and implantable artificial kidney devices for end-stage kidney disease treatment-Current status and review. Artif Organs 2022; 47:649-666. [PMID: 36129158 DOI: 10.1111/aor.14396] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Revised: 08/17/2022] [Accepted: 08/24/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND Chronic kidney disease (CKD) is a major cause of early death worldwide. By 2030, 14.5 million people will have end-stage kidney disease (ESKD, or CKD stage 5), yet only 5.4 million will receive kidney replacement therapy (KRT) due to economic, social, and political factors. Even for those who are offered KRT by various means of dialysis, the life expectancy remains far too low. OBSERVATION Researchers from different fields of artificial organs collaborate to overcome the challenges of creating products such as Wearable and/or Implantable Artificial Kidneys capable of providing long-term effective physiologic kidney functions such as removal of uremic toxins, electrolyte homeostasis, and fluid regulation. A focus should be to develop easily accessible, safe, and inexpensive KRT options that enable a good quality of life and will also be available for patients in less-developed regions of the world. CONCLUSIONS Hence, it is required to discuss some of the limits and burdens of transplantation and different techniques of dialysis, including those performed at home. Furthermore, hurdles must be considered and overcome to develop wearable and implantable artificial kidney devices that can help to improve the quality of life and life expectancy of patients with CKD.
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Affiliation(s)
- Thomas Groth
- Department Biomedical Materials, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.,International Federation for Artificial Organs, Painesville, Ohio, USA
| | - Bernd G Stegmayr
- Department of Public Health and Clinical Medicine, Umea University, Umea, Sweden
| | | | - Janna Kuchinka
- Department Biomedical Materials, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Fokko P Wieringa
- IMEC, Eindhoven, The Netherlands.,Department of Nephrology, University Medical Centre, Utrecht, The Netherlands.,European Kidney Health Alliance, WG3 "Breakthrough Innovation", Brussels, Belgium
| | | | - Shuvo Roy
- University of California, California, San Francisco, USA
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21
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Pierson RN, Allan JS, Cooper DK, D’Alessandro DA, Fishman JA, Kawai T, Lewis GD, Madsen JC, Markmann JF, Riella LV. Expert Opinion Special Feature: Patient Selection for Initial Clinical Trials of Pig Organ Transplantation. Transplantation 2022; 106:1720-1723. [PMID: 35761442 PMCID: PMC10124765 DOI: 10.1097/tp.0000000000004197] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Richard N. Pierson
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - James S. Allan
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - David K.C. Cooper
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - David A. D’Alessandro
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Jay A. Fishman
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Tatsuo Kawai
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Gregory D. Lewis
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Joren C. Madsen
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - James F. Markmann
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Leonardo V. Riella
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA
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22
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Zhou Q, Li T, Wang K, Zhang Q, Geng Z, Deng S, Cheng C, Wang Y. Current status of xenotransplantation research and the strategies for preventing xenograft rejection. Front Immunol 2022; 13:928173. [PMID: 35967435 PMCID: PMC9367636 DOI: 10.3389/fimmu.2022.928173] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 07/07/2022] [Indexed: 12/13/2022] Open
Abstract
Transplantation is often the last resort for end-stage organ failures, e.g., kidney, liver, heart, lung, and pancreas. The shortage of donor organs is the main limiting factor for successful transplantation in humans. Except living donations, other alternatives are needed, e.g., xenotransplantation of pig organs. However, immune rejection remains the major challenge to overcome in xenotransplantation. There are three different xenogeneic types of rejections, based on the responses and mechanisms involved. It includes hyperacute rejection (HAR), delayed xenograft rejection (DXR) and chronic rejection. DXR, sometimes involves acute humoral xenograft rejection (AHR) and cellular xenograft rejection (CXR), which cannot be strictly distinguished from each other in pathological process. In this review, we comprehensively discussed the mechanism of these immunological rejections and summarized the strategies for preventing them, such as generation of gene knock out donors by different genome editing tools and the use of immunosuppressive regimens. We also addressed organ-specific barriers and challenges needed to pave the way for clinical xenotransplantation. Taken together, this information will benefit the current immunological research in the field of xenotransplantation.
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Affiliation(s)
- Qiao Zhou
- Department of Rheumatology and Immunology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
| | - Ting Li
- Department of Rheumatology, Wenjiang District People’s Hospital, Chengdu, China
| | - Kaiwen Wang
- School of Medicine, Faculty of Medicine and Health, The University of Leeds, Leeds, United Kingdom
| | - Qi Zhang
- School of Medicine, University of Electronics and Technology of China, Chengdu, China
| | - Zhuowen Geng
- School of Medicine, Faculty of Medicine and Health, The University of Leeds, Leeds, United Kingdom
| | - Shaoping Deng
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China
- Chinese Academy of Sciences Sichuan Translational Medicine Research Hospital, Chengdu, China
- Institute of Organ Transplantation, Sichuan Academy of Medical Science and Sichuan Provincial People’s Hospital, Chengdu, China
| | - Chunming Cheng
- Department of Radiation Oncology, James Comprehensive Cancer Center and College of Medicine at The Ohio State University, Columbus, OH, United States
- *Correspondence: Chunming Cheng, ; Yi Wang,
| | - Yi Wang
- Department of Critical Care Medicine, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, Chengdu, China
- *Correspondence: Chunming Cheng, ; Yi Wang,
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23
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Huang B, Zeng Z, Zhang CC, Schreiber ME, Li Z. Approaches to kidney replacement therapies—opportunities and challenges. Front Cell Dev Biol 2022; 10:953408. [PMID: 35982852 PMCID: PMC9380013 DOI: 10.3389/fcell.2022.953408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 07/01/2022] [Indexed: 11/29/2022] Open
Abstract
One out of seven people develop chronic kidney disease (CKD). When kidney function continues to decline, CKD patients may develop end-stage renal disease (ESRD, or kidney failure). More than 2 out of 1,000 adults develop ESRD and these patients must live on dialysis or get a kidney transplant to survive. Each year, more than $51 billion is spent to treat patients with ESRD in the United States. In addition, ESRD greatly reduces longevity and quality of life for patients. Compared to dialysis, kidney transplant offers the best chance of survival, but few donor organs are available. Thus, there is an urgent need for innovative solutions that address the shortage of kidneys available for transplantation. Here we summarize the status of current approaches that are being developed to solve the shortage of donor kidneys. These include the bioartificial kidney approach which aims to make a portable dialysis device, the recellularization approach which utilizes native kidney scaffold to make an engineered kidney, the stem cell-based approach which aims to generate a kidney de novo by recapitulating normal kidney organogenesis, the xenotransplantation approach which has the goal to make immunocompatible pig kidneys for transplantation, and the interspecies chimera approach which has potential to generate a human kidney in a host animal. We also discuss the interconnections among the different approaches, and the remaining challenges of translating these approaches into novel therapies.
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Affiliation(s)
- Biao Huang
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Deptartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Zipeng Zeng
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Deptartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Chennan C. Zhang
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Deptartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Megan E. Schreiber
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Deptartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Zhongwei Li
- USC/UKRO Kidney Research Center, Division of Nephrology and Hypertension, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- Deptartment of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
- *Correspondence: Zhongwei Li,
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24
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Abstract
Xenotransplantation has seen recent global interest peak as a result of several clinical xenotransplants being performed in decedents and a live cardiac recipient. However, underpinning these latest transplants have been decades of invested scientific research programs that have been developing the ideal donor source animals to avoid the overwhelming hyperacute xenograft rejection seen using nongenetically modified animal organs, tissues, and cells. However, this also needs to be undertaken along with the development of safe and efficacious xenotransplantation technologies, immunosuppression, monitoring, disease screening, patient selection, societal education, and acceptance. Paralleling the advent of such extraordinary transplants have been several decades of establishment of world xenotransplantation authorities such as the International Xenotransplantation Association, and the development of guidance documents and regulations for the assessment of these cutting-edge technologies. Similar to all new technologies there remain outdated concerns and fears of the theoretical potential for transmission of xenozoonosis, ethical concerns, and outdated or appropriately educated societal concerns and religious views of the benefits or risks and issues for xenotransplantation use of organs, tissues, or cells from animals to human beings. Here, we discuss the development of xenotransplantation and the intricate balance in managing the various challenges with which we are faced: in the absolute benefits of xenotransplantation and the dichotomy in balancing the pros and cons of xenotransplantation with social, religious, ethical, scientific, and medical opinions. Ultimately, the benefits are to those patients suffering from the many and various diseases that drive the need for xenotransplantation. The hope is that it will be implemented as soon as possible to help the many millions of patients who can truly benefit.
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25
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Carrier AN, Verma A, Mohiuddin M, Pascual M, Muller YD, Longchamp A, Bhati C, Buhler LH, Maluf DG, Meier RPH. Xenotransplantation: A New Era. Front Immunol 2022; 13:900594. [PMID: 35757701 PMCID: PMC9218200 DOI: 10.3389/fimmu.2022.900594] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
Organ allotransplantation has now reached an impassable ceiling inherent to the limited supply of human donor organs. In the United States, there are currently over 100,000 individuals on the national transplant waiting list awaiting a kidney, heart, and/or liver transplant. This is in contrast with only a fraction of them receiving a living or deceased donor allograft. Given the morbidity, mortality, costs, or absence of supportive treatments, xenotransplant has the potential to address the critical shortage in organ grafts. Last decade research efforts focused on creation of donor organs from pigs with various genes edited out using CRISPR technologies and utilizing non-human primates for trial. Three groups in the United States have recently moved forward with trials in human subjects and obtained initial successful results with pig-to-human heart and kidney xenotransplantation. This review serves as a brief discussion of the recent progress in xenotransplantation research, particularly as it concerns utilization of porcine heart, renal, and liver xenografts in clinical practice.
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Affiliation(s)
- Amber N Carrier
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Anjali Verma
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Muhammad Mohiuddin
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Manuel Pascual
- Department of Vascular Surgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
| | - Yannick D Muller
- Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
| | - Alban Longchamp
- Department of Vascular Surgery, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland
| | - Chandra Bhati
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Leo H Buhler
- Faculty of Science and Medicine, Section of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Daniel G Maluf
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States
| | - Raphael P H Meier
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, United States
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26
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Saito Y, Yamanaka S, Matsumoto N, Takamura T, Fujimoto T, Matsui K, Tajiri S, Matsumoto K, Kobayashi E, Yokoo T. Generation of functional chimeric kidney containing exogenous progenitor-derived stroma and nephron via a conditional empty niche. Cell Rep 2022; 39:110933. [PMID: 35705028 DOI: 10.1016/j.celrep.2022.110933] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 03/31/2022] [Accepted: 05/18/2022] [Indexed: 11/17/2022] Open
Abstract
Generation of new kidneys can be useful in various research fields, including organ transplantation. However, generating renal stroma, an important component tissue for structural support, endocrine function, and kidney development, remains difficult. Organ generation using an animal developmental niche can provide an appropriate in vivo environment for renal stroma differentiation. Here, we generate rat renal stroma with endocrine capacity by removing mouse stromal progenitor cells (SPCs) from the host developmental niche and transplanting rat SPCs. Furthermore, we develop a method to replace both nephron progenitor cells (NPCs) and SPCs, called the interspecies dual replacement of the progenitor (i-DROP) system, and successfully generate functional chimeric kidneys containing rat nephrons and stroma. This method can generate renal tissue from progenitors and reduce xenotransplant rejection. Moreover, it is a safe method, as donor cells do not stray into nontarget organs, thus accelerating research on stem cells, chimeras, and xenotransplantation.
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Affiliation(s)
- Yatsumu Saito
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Shuichiro Yamanaka
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Naoto Matsumoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Tsuyoshi Takamura
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Toshinari Fujimoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kenji Matsui
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Susumu Tajiri
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kei Matsumoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Eiji Kobayashi
- Department of Kidney Regenerative Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.
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27
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Saito Y, Matsumoto N, Yamanaka S, Yokoo T, Kobayashi E. Beneficial Impact of Interspecies Chimeric Renal Organoids Against a Xenogeneic Immune Response. Front Immunol 2022; 13:848433. [PMID: 35242145 PMCID: PMC8885510 DOI: 10.3389/fimmu.2022.848433] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 01/24/2022] [Indexed: 11/25/2022] Open
Abstract
Background Animal fetal kidneys have the potential to be used as scaffolds for organ regeneration. We generated interspecies chimeric renal organoids by adding heterologous rat renal progenitor cells to single cells from mouse fetal kidneys and applying the renal development mechanism of mouse fetuses to rat renal progenitor cells to examine whether rat renal progenitor cells can differentiate into renal tissues of the three progenitor cell lineages of kidneys between different species. Furthermore, we investigated whether chimeric renal organoids with an increased proportion of recipient cells reduce xenogeneic rejection. Methods C57BL/6JJmsSlc mice (B6 mice) and Sprague-Dawley-Tg (CAG-EGFP) rat (GFP rats) fetuses were used as donors, and mature male NOD/Shi-scid, IL-2RγKO Jic mice (NOG mice) and Sprague-Dawley rats (SD rats) were used as recipients. First, fetal kidneys were removed from E13.5 B6 mice or E15.5 GFP rats and enzymatically dissociated into single cells. These cells were then mixed in equal proportions to produce chimeric renal organoids in vitro. The chimeric organoids were transplanted under the renal capsule of NOG mice, and maturation of the renal tissues in the organoids was observed histologically. Furthermore, chimeric organoids were prepared by changing the ratio of cells derived from mouse and rat fetal kidneys and transplanted under the renal capsule of SD rats subjected to mild immunosuppression to pathologically analyze the strength of the xenogeneic immune response. Results The cap mesenchyme was reconstructed in vitro, and nephron progenitor cells and ureteric buds were mosaically comprised GFP-negative mouse and GFP-positive rat cells. In the in vivo environment of immunodeficient mice, chimeric renal organoids mosaically differentiated and matured into renal tissues of three lineages. Chimeric renal organoids with high rates of recipient rat cells showed milder rejection than complete xenograft organoids. The vessels of recipient rats entered from the periphery of the transplanted chimeric renal organoids, which might reduce their immunogenicity. Conclusion Interspecies chimeric renal organoids may differentiate into mature renal tissues of each renal progenitor cell lineage. Furthermore, they may reduce transplant rejection compared with xenograft organoids.
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Affiliation(s)
- Yatsumu Saito
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Naoto Matsumoto
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Shuichiro Yamanaka
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Takashi Yokoo
- Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Eiji Kobayashi
- Department of Kidney Regenerative Medicine, The Jikei University School of Medicine, Tokyo, Japan
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28
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Feng H, Li T, Du J, Xia Q, Wang L, Chen S, Zhu L, Pan D, Wang Y, Chen G. Both Natural and Induced Anti-Sda Antibodies Play Important Roles in GTKO Pig-to-Rhesus Monkey Xenotransplantation. Front Immunol 2022; 13:849711. [PMID: 35422817 PMCID: PMC9004458 DOI: 10.3389/fimmu.2022.849711] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Accepted: 03/07/2022] [Indexed: 01/30/2023] Open
Abstract
Sda, produced by the B4GALNT2 enzyme, has been recognized as an important xenoantigen for pig-to-nonhuman primate xenotransplantation. However, little is known about Sda expression in pigs and its immunogenicity in xenotransplantation. In this study, peripheral blood mononuclear cells (PBMCs) were isolated from wildtype, GTKO (with high, moderate, and low Sda expression), GTKO/β4GalNT2KO, GTKO/CMAHKO, or GTKO/CMAHKO/β4GalNT2KO pigs. Anti-pig IgM/IgG binding and complement-dependent cytotoxicity (CDC) to pig PBMCs was measured by flow cytometry using pooled rhesus monkey sera (n=20) or human sera (n=20). As compared to wild-type pigs (n=12), GTKO pigs (n=17) had a significantly higher mean level of Sda expression on PBMCs and showed a greater individual difference in expression. Both the overall binding of monkey serum IgM/IgG antibody to GTKO pig PBMCs and CDC against these PBMCs decreased significantly with a progressive reduction in Sda expression, showing a clear dose-effect relationship. Both the monkey serum antibody binding and CDC decreased significantly after the additional deletion of Sda, whereas the binding of human serum antibody and CDC against the GTKO pig PBMCs were markedly reduced after the deletion of Neu5Gc in the pigs. In addition, anti-Sda antibody accounted for > 50% of the induced anti-non-Gal antibody at the time of rejection in two rhesus monkeys that received GTKO/hCD55 pig kidney xenotransplantation, and the anti-Sda antibody showed significant cytotoxic activity against GTKO pig cells. We conclude that both natural and induced anti-Sda antibodies play important roles in GTKO pig-to-rhesus monkey xenotransplantation, thus providing further evidence for GTKO/β4GalNT2KO pigs as the preferred organ source for rhesus monkeys as a preclinical model of xenotransplantation.
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Affiliation(s)
- Hao Feng
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Tao Li
- Department of Organ Transplantation, The Transplantation Institute of Hainan Medical University, The Second Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Jiaxiang Du
- Genetic Engineering Department, Chengdu Clonorgan Biotechnology Co., Ltd, Chengdu, China
| | - Qiangbing Xia
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Lu Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Song Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Lan Zhu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Dengke Pan
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Yi Wang
- Department of Organ Transplantation, The Transplantation Institute of Hainan Medical University, The Second Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Gang Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
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29
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Feng H, Li T, Du J, Xia Q, Wang L, Chen S, Zhu L, Pan D, Wang Y, Chen G. Both Natural and Induced Anti-Sda Antibodies Play Important Roles in GTKO Pig-to-Rhesus Monkey Xenotransplantation. Front Immunol 2022. [DOI: 10.3389/fimmu.2022.849711
expr 981672748 + 872648996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Sda, produced by the B4GALNT2 enzyme, has been recognized as an important xenoantigen for pig-to-nonhuman primate xenotransplantation. However, little is known about Sda expression in pigs and its immunogenicity in xenotransplantation. In this study, peripheral blood mononuclear cells (PBMCs) were isolated from wildtype, GTKO (with high, moderate, and low Sda expression), GTKO/β4GalNT2KO, GTKO/CMAHKO, or GTKO/CMAHKO/β4GalNT2KO pigs. Anti-pig IgM/IgG binding and complement-dependent cytotoxicity (CDC) to pig PBMCs was measured by flow cytometry using pooled rhesus monkey sera (n=20) or human sera (n=20). As compared to wild-type pigs (n=12), GTKO pigs (n=17) had a significantly higher mean level of Sda expression on PBMCs and showed a greater individual difference in expression. Both the overall binding of monkey serum IgM/IgG antibody to GTKO pig PBMCs and CDC against these PBMCs decreased significantly with a progressive reduction in Sda expression, showing a clear dose-effect relationship. Both the monkey serum antibody binding and CDC decreased significantly after the additional deletion of Sda, whereas the binding of human serum antibody and CDC against the GTKO pig PBMCs were markedly reduced after the deletion of Neu5Gc in the pigs. In addition, anti-Sda antibody accounted for > 50% of the induced anti-non-Gal antibody at the time of rejection in two rhesus monkeys that received GTKO/hCD55 pig kidney xenotransplantation, and the anti-Sda antibody showed significant cytotoxic activity against GTKO pig cells. We conclude that both natural and induced anti-Sda antibodies play important roles in GTKO pig-to-rhesus monkey xenotransplantation, thus providing further evidence for GTKO/β4GalNT2KO pigs as the preferred organ source for rhesus monkeys as a preclinical model of xenotransplantation.
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30
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Recchia K, Machado LS, Botigelli RC, Pieri NCG, Barbosa G, de Castro RVG, Marques MG, Pessôa LVDF, Fantinato Neto P, Meirelles FV, Souza AFD, Martins SMMK, Bressan FF. In vitro induced pluripotency from urine-derived cells in porcine. World J Stem Cells 2022; 14:231-244. [PMID: 35432738 PMCID: PMC8968213 DOI: 10.4252/wjsc.v14.i3.231] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 10/11/2021] [Accepted: 02/16/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The generation of induced pluripotent stem cells (iPSC) has been a game-changer in translational and regenerative medicine; however, their large-scale applicability is still hampered by the scarcity of accessible, safe, and reproducible protocols. The porcine model is a large biomedical model that enables translational applications, including gene editing, long term in vivo and offspring analysis; therefore, suitable for both medicine and animal production.
AIM To reprogramme in vitro into pluripotency, and herein urine-derived cells (UDCs) were isolated from porcine urine.
METHODS The UDCs were reprogrammed in vitro using human or murine octamer-binding transcription factor 4 (OCT4), SRY-box2 (SOX2), Kruppel-like factor 4 (KLF4), and C-MYC, and cultured with basic fibroblast growth factor (bFGF) supplementation. To characterize the putative porcine iPSCs three clonal lineages were submitted to immunocytochemistry for alkaline phosphatase (AP), OCT4, SOX2, NANOG, TRA1 81 and SSEA 1 detection. Endogenous transcripts related to the pluripotency (OCT4, SOX2 and NANOG) were analyzed via reverse transcription quantitative real-time polymerase chain reaction in different time points during the culture, and all three lineages formed embryoid bodies (EBs) when cultured in suspension without bFGF supplementation.
RESULTS The UDCs were isolated from swine urine samples and when at passage 2 submitted to in vitro reprogramming. Colonies of putative iPSCs were obtained only from UDCs transduced with the murine factors (mOSKM), but not from human factors (hOSKM). Three clonal lineages were isolated and further cultured for at least 28 passages, all the lineages were positive for AP detection, the OCT4, SOX2, NANOG markers, albeit the immunocytochemical analysis also revealed heterogeneous phenotypic profiles among lineages and passages for NANOG and SSEA1, similar results were observed in the abundance of the endogenous transcripts related to pluripotent state. All the clonal lineages when cultured in suspension without bFGF were able to form EBs expressing ectoderm and mesoderm layers transcripts.
CONCLUSION For the first time UDCs were isolated in the swine model and reprogrammed into a pluripotent-like state, enabling new numerous applications in both human or veterinary regenerative medicine.
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Affiliation(s)
- Kaiana Recchia
- Department of Surgery, Faculty of Veterinary Medicine and Animal Sciences, University of São Paulo, Pirassununga 13635-000, São Paulo, Brazil
| | - Lucas Simões Machado
- Department of Surgery, Faculty of Veterinary Medicine and Animal Sciences, University of São Paulo, Pirassununga 13635-000, São Paulo, Brazil
| | - Ramon Cesar Botigelli
- Department of Pharmacology and Biotechnology, Institute of Bioscience, São Paulo State University, Botucatu 18618-689, São Paulo, Brazil
| | - Naira Caroline Godoy Pieri
- Department of Veterinary Medicine, Faculty of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga 13635-000, São Paulo, Brazil
| | - Gabriela Barbosa
- Department of Veterinary Medicine, Faculty of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga 13635-000, São Paulo, Brazil
| | | | - Mariana Groke Marques
- Embrapa Suínos e Aves, Empresa Brasileira de Pesquisa Agropecuária, Concordia 89715-899, Santa Catarina, Brazil
| | - Laís Vicari de Figueiredo Pessôa
- Department of Veterinary Medicine, Faculty of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga 13635-000, São Paulo, Brazil
| | - Paulo Fantinato Neto
- Department of Veterinary Medicine, Faculty of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga 13635-000, São Paulo, Brazil
| | - Flávio Vieira Meirelles
- Department of Surgery, Faculty of Veterinary Medicine and Animal Sciences, University of São Paulo, Pirassununga 13635-000, São Paulo, Brazil
- Department of Veterinary Medicine, Faculty of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga 13635-000, São Paulo, Brazil
| | - Aline Fernanda de Souza
- Department of Veterinary Medicine, Faculty of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga 13635-000, São Paulo, Brazil
| | | | - Fabiana Fernandes Bressan
- Department of Surgery, Faculty of Veterinary Medicine and Animal Sciences, University of São Paulo, Pirassununga 13635-000, São Paulo, Brazil
- Department of Veterinary Medicine, Faculty of Animal Sciences and Food Engineering, University of São Paulo, Pirassununga 13635-000, São Paulo, Brazil
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31
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Fang X, Tanga BM, Bang S, Seong G, Saadeldin IM, Qamar AY, Shim J, Choi K, Lee S, Cho J. Vitamin C enhances porcine cloned embryo development and improves the derivation of embryonic stem-like cells. Reprod Biol 2022; 22:100632. [PMID: 35334451 DOI: 10.1016/j.repbio.2022.100632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/17/2022] [Accepted: 02/21/2022] [Indexed: 11/24/2022]
Abstract
Porcine cloning through somatic cell nuclear transfer (SCNT) has been widely used in biotechnology for generating animal disease models and genetically modified animals for xenotransplantation. Vitamin C is a multifunctional factor that reacts with several enzymes. In this study, we used porcine oocytes to investigate the effects of different concentrations of vitamin C on in vitro maturation (IVM), in vitro culture (IVC), and the derivation of nuclear transfer embryonic stem-like cells (NT-ESCs). We demonstrated that vitamin C promoted the cleavage and blastocyst rate of genetically modified cloned porcine embryos and improved the derivation of NT-ESCs. Vitamin C integrated into IVM and IVC enhanced cleavage and blastocyst formation (P < 0.05) in SCNT embryos. Glutathione level was increased, and reactive oxygen species levels were decreased (P < 0.05) due to vitamin C treatment. Vitamin C decreased the gene expression of apoptosis (BAX) and increased the expression of genes associated with nuclear reprogramming (NANOG, POU5F1, SOX2, c-Myc, Klf4, and TEAD4), antioxidation (SOD1), anti-apoptotic (Bcl2), and trophectoderm (CDX2). Moreover, vitamin C improved the attachment, derivation, and passaging of NT-ESCs, while the control group showed no outgrowths beyond the primary culture. In conclusion, supplementation of vitamin C at a dose of 50 µg/ml to the IVM and IVC culture media was appropriate to improve the outcomes of porcine IVM and IVC and for the derivation of NT-ESCs as a model to study the pre- and post-implantation embryonic development in cloned transgenic embryos. Therefore, we recommend the inclusion of vitamin C as a supplementary factor to IVM and IVC to improve porcine in vitro embryonic development.
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Affiliation(s)
- Xun Fang
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Bereket Molla Tanga
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Seonggyu Bang
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Gyeonghwan Seong
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Islam M Saadeldin
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea; Research Institute of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Ahmad Yar Qamar
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Joohyun Shim
- Department of Transgenic Animal Research, Optipharm, Inc., Chungcheongbuk-do, Cheongju-si, Republic of Korea
| | - Kimyung Choi
- Department of Transgenic Animal Research, Optipharm, Inc., Chungcheongbuk-do, Cheongju-si, Republic of Korea
| | - Sanghoon Lee
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea
| | - Jongki Cho
- Laboratory of Theriogenology, College of Veterinary Medicine, Chungnam National University, Daejeon, Republic of Korea.
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32
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Koehler N, Buhler L, Egger B, Gonelle-Gispert C. Multipotent Mesenchymal Stromal Cells Interact and Support Islet of Langerhans Viability and Function. Front Endocrinol (Lausanne) 2022; 13:822191. [PMID: 35222280 PMCID: PMC8864309 DOI: 10.3389/fendo.2022.822191] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 01/13/2022] [Indexed: 11/13/2022] Open
Abstract
Type 1 diabetes (T1D) is a widespread disease, affecting approximately 41.5 million people worldwide. It is generally treated with exogenous insulin, maintaining physiological blood glucose levels but also leading to long-term therapeutic complications. Pancreatic islet cell transplantation offers a potential alternative treatment to insulin injections. Shortage of human organ donors has raised the interest for porcine islet xenotransplantation. Neonatal porcine islets are highly available, can proliferate and mature in vitro as well as after transplantation in vivo. Despite promising preclinical results, delayed insulin secretion caused by immaturity and immunogenicity of the neonatal porcine islets remains a challenge for their clinical application. Multipotent mesenchymal stromal cells (MSCs) are known to have pro-angiogenic, anti-inflammatory and immunomodulatory effects. The current state of research emphasizes the great potential of co-culture and co-transplantation of islet cells with MSCs. Studies have shown enhanced islet proliferation and maturation, insulin secretion and graft survival, resulting in an improved graft outcome. This review summarizes the immunomodulatory and anti-inflammatory properties of MSC in the context of islet transplantation.
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Affiliation(s)
- Naomi Koehler
- Surgical Research Unit, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
| | - Leo Buhler
- Department of Surgery, Cantonal Hospital Fribourg, Fribourg, Switzerland
| | - Bernhard Egger
- Surgical Research Unit, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
- Department of Surgery, Cantonal Hospital Fribourg, Fribourg, Switzerland
| | - Carmen Gonelle-Gispert
- Surgical Research Unit, Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland
- *Correspondence: Carmen Gonelle-Gispert,
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Feng H, Li T, Du J, Xia Q, Wang L, Chen S, Zhu L, Pan D, Wang Y, Chen G. Both Natural and Induced Anti-Sda Antibodies Play Important Roles in GTKO Pig-to-Rhesus Monkey Xenotransplantation. Front Immunol 2022. [PMID: 35422817 PMCID: PMC9004458 DOI: 10.3389/fimmu.2022.849711&set/a 866800723+810249609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2023] Open
Abstract
Sda, produced by the B4GALNT2 enzyme, has been recognized as an important xenoantigen for pig-to-nonhuman primate xenotransplantation. However, little is known about Sda expression in pigs and its immunogenicity in xenotransplantation. In this study, peripheral blood mononuclear cells (PBMCs) were isolated from wildtype, GTKO (with high, moderate, and low Sda expression), GTKO/β4GalNT2KO, GTKO/CMAHKO, or GTKO/CMAHKO/β4GalNT2KO pigs. Anti-pig IgM/IgG binding and complement-dependent cytotoxicity (CDC) to pig PBMCs was measured by flow cytometry using pooled rhesus monkey sera (n=20) or human sera (n=20). As compared to wild-type pigs (n=12), GTKO pigs (n=17) had a significantly higher mean level of Sda expression on PBMCs and showed a greater individual difference in expression. Both the overall binding of monkey serum IgM/IgG antibody to GTKO pig PBMCs and CDC against these PBMCs decreased significantly with a progressive reduction in Sda expression, showing a clear dose-effect relationship. Both the monkey serum antibody binding and CDC decreased significantly after the additional deletion of Sda, whereas the binding of human serum antibody and CDC against the GTKO pig PBMCs were markedly reduced after the deletion of Neu5Gc in the pigs. In addition, anti-Sda antibody accounted for > 50% of the induced anti-non-Gal antibody at the time of rejection in two rhesus monkeys that received GTKO/hCD55 pig kidney xenotransplantation, and the anti-Sda antibody showed significant cytotoxic activity against GTKO pig cells. We conclude that both natural and induced anti-Sda antibodies play important roles in GTKO pig-to-rhesus monkey xenotransplantation, thus providing further evidence for GTKO/β4GalNT2KO pigs as the preferred organ source for rhesus monkeys as a preclinical model of xenotransplantation.
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Affiliation(s)
- Hao Feng
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Tao Li
- Department of Organ Transplantation, The Transplantation Institute of Hainan Medical University, The Second Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Jiaxiang Du
- Genetic Engineering Department, Chengdu Clonorgan Biotechnology Co., Ltd, Chengdu, China
| | - Qiangbing Xia
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Lu Wang
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Song Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Lan Zhu
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
| | - Dengke Pan
- Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
| | - Yi Wang
- Department of Organ Transplantation, The Transplantation Institute of Hainan Medical University, The Second Affiliated Hospital of Hainan Medical University, Hainan, China
| | - Gang Chen
- Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Key Laboratory of Organ Transplantation, Ministry of Education and National Health Commission (NHC), Chinese Academy of Medical Sciences, Wuhan, China
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34
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Hurst DJ, Padilla LA, Cooper DKC, Paris W. Scientific and psychosocial ethical considerations for initial clinical trials of kidney xenotransplantation. Xenotransplantation 2021; 29:e12722. [PMID: 34800313 DOI: 10.1111/xen.12722] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 09/23/2021] [Accepted: 10/21/2021] [Indexed: 12/28/2022]
Abstract
The initial clinical trials of pig solid organ xenotransplantation (XTx) are drawing closer and could begin in the coming years. The first clinical trials may aim to transplant genetically-modified pig kidneys into adult humans. The impetus for beginning these first-in-human trials is the severe lack of deceased donor kidneys for transplantation and the number of patients with end-stage renal disease currently on transplant waitlists, which in the USA approaches 100 000. The majority of patients on the kidney transplant waitlist receive continuous renal replacement therapy. In the United States, for patients on the kidney waitlist, the median wait-time to receive a deceased human donor organ is approximately 4.5 years for patients aged 45-74, with a 5-year mortality (or removal from the waitlist because of deteriorating health) of approximately 40%. XTx has the potential to reduce the kidney waitlist morbidity and mortality while improving quality of life. By focusing on scientific and psychosocial criteria, we present ethical considerations of certain inclusion and exclusion criteria for these first-in-human clinical trials that we suggest have not yet been fully explored.
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Affiliation(s)
- Daniel J Hurst
- Department of Family Medicine, Rowan University School of Osteopathic Medicine, Stratford, New Jersey, USA
| | - Luz A Padilla
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - David K C Cooper
- Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Wayne Paris
- School of Social Work, Abilene Christian University, Abilene, Texas, USA
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35
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Bikhet M, Iwase H, Yamamoto T, Jagdale A, Foote JB, Ezzelarab M, Anderson DJ, Locke JE, Eckhoff DE, Hara H, Cooper DKC. What Therapeutic Regimen Will Be Optimal for Initial Clinical Trials of Pig Organ Transplantation? Transplantation 2021; 105:1143-1155. [PMID: 33534529 DOI: 10.1097/tp.0000000000003622] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We discuss what therapeutic regimen might be acceptable/successful in the first clinical trial of genetically engineered pig kidney or heart transplantation. As regimens based on a calcineurin inhibitor or CTLA4-Ig have proved unsuccessful, the regimen we administer to baboons is based on induction therapy with antithymocyte globulin, an anti-CD20 mAb (Rituximab), and cobra venom factor, with maintenance therapy based on blockade of the CD40/CD154 costimulation pathway (with an anti-CD40 mAb), with rapamycin, and a corticosteroid. An anti-inflammatory agent (etanercept) is administered for the first 2 wk, and adjuvant therapy includes prophylaxis against thrombotic complications, anemia, cytomegalovirus, and pneumocystis. Using this regimen, although antibody-mediated rejection certainly can occur, we have documented no definite evidence of an adaptive immune response to the pig xenograft. This regimen could also form the basis for the first clinical trial, except that cobra venom factor will be replaced by a clinically approved agent, for example, a C1-esterase inhibitor. However, none of the agents that block the CD40/CD154 pathway are yet approved for clinical use, and so this hurdle remains to be overcome. The role of anti-inflammatory agents remains unproven. The major difference between this suggested regimen and those used in allotransplantation is the replacement of a calcineurin inhibitor with a costimulation blockade agent, but this does not appear to increase the complications of the regimen.
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Affiliation(s)
- Mohamed Bikhet
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Hayato Iwase
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Takayuki Yamamoto
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Abhijit Jagdale
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Jeremy B Foote
- Department of Microbiology and Animal Resources Program, University of Alabama at Birmingham, Birmingham, AL
| | - Mohamed Ezzelarab
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Douglas J Anderson
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Jayme E Locke
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Devin E Eckhoff
- Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Hidetaka Hara
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - David K C Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
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36
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Kaur G, Wright K, Mital P, Hibler T, Miranda JM, Thompson LA, Halley K, Dufour JM. Neonatal Pig Sertoli Cells Survive Xenotransplantation by Creating an Immune Modulatory Environment Involving CD4 and CD8 Regulatory T Cells. Cell Transplant 2021; 29:963689720947102. [PMID: 32841048 PMCID: PMC7564626 DOI: 10.1177/0963689720947102] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
The acute cell-mediated immune response presents a significant barrier to
xenotransplantation. Immune-privileged Sertoli cells (SC) can prolong the
survival of co-transplanted cells including xenogeneic islets, hepatocytes, and
neurons by protecting them from immune rejection. Additionally, SC survive as
allo- and xenografts without the use of any immunosuppressive drugs suggesting
elucidating the survival mechanism(s) of SC could be used to improve survival of
xenografts. In this study, the survival and immune response generated toward
neonatal pig SC (NPSC) or neonatal pig islets (NPI), nonimmune-privileged
controls, was compared after xenotransplantation into naïve Lewis rats without
immune suppression. The NPSC survived throughout the study, while NPI were
rejected within 9 days. Analysis of the grafts revealed that macrophages and T
cells were the main immune cells infiltrating the NPSC and NPI grafts. Further
characterization of the T cells within the grafts indicated that the NPSC grafts
contained significantly more cluster of differentiation 4 (CD4) and cluster of
differentiation 8 (CD8) regulatory T cells (Tregs) at early time points than the
NPI grafts. Additionally, the presence of increased amounts of interleukin 10
(IL-10) and transforming growth factor (TGF) β and decreased levels of tumor
necrosis factor (TNF) α and apoptosis in the NPSC grafts compared to NPI grafts
suggests the presence of regulatory immune cells in the NPSC grafts. The NPSC
expressed several immunoregulatory factors such as TGFβ, thrombospondin-1
(THBS1), indoleamine-pyrrole 2,3-dioxygenase, and galectin-1, which could
promote the recruitment of these regulatory immune cells to the NPSC grafts. In
contrast, NPI grafts had fewer Tregs and increased apoptosis and inflammation
(increased TNFα, decreased IL-10 and TGFβ) suggestive of cytotoxic immune cells
that contribute to their early rejection. Collectively, our data suggest that a
regulatory graft environment with regulatory immune cells including CD4 and
CD8 Tregs in NPSC grafts could be attributed to the prolonged survival of the
NPSC xenografts.
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Affiliation(s)
- Gurvinder Kaur
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA.,Department of Medical Education, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Kandis Wright
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Payal Mital
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Taylor Hibler
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Jonathan M Miranda
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Lea Ann Thompson
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Katelyn Halley
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
| | - Jannette M Dufour
- Department of Cell Biology and Biochemistry, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA.,Department of Medical Education, 12343Texas Tech University Health Sciences Center, Lubbock, TX, USA
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Hara H, Nguyen H, Wang ZY, Jagdale A, Bikhet M, Yamamoto T, Iwase H, Ayares D, Cooper DKC. Evidence that sensitization to triple-knockout pig cells will not be detrimental to subsequent allotransplantation. Xenotransplantation 2021; 28:e12701. [PMID: 34053125 DOI: 10.1111/xen.12701] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/22/2021] [Accepted: 05/10/2021] [Indexed: 11/28/2022]
Abstract
The current evidence is that sensitization to a pig xenograft does not result in the development of antibodies that cross-react with alloantigens, and therefore, sensitization to a pig xenograft would not be detrimental to the outcome of a subsequent allograft. This evidence relates almost entirely to the transplantation of cells or organs from wild-type or α1,3-galactosyltransferase gene-knockout (GTKO) pigs. However, it is not known whether recipients of triple-knockout (TKO) pig grafts who become sensitized to TKO pig antigens develop antibodies that cross-react with alloantigens and thus be detrimental to a subsequent organ allotransplant. We identified a single baboon (B1317) in which no (or minimal) serum anti-TKO pig antibodies could be measured-in our experience unique among baboons. We sensitized it by repeated subcutaneous injections of TKO pig peripheral blood mononuclear cells (PBMCs) in the absence of any immunosuppressive therapy. After TKO pig PBMC injection, there was a transient increase in anti-TKO pig IgM, followed by a sustained increase in IgG binding to TKO cells. In contrast, there was no serum IgM or IgG binding to PBMCs from any of a panel of baboon PBMCs (n = 8). We conclude that sensitization to TKO pig PBMCs in the baboon did not result in the development of antibodies that also bound to baboon cells, suggesting that there would be no detrimental effect of sensitization on a subsequent organ allotransplant.
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Affiliation(s)
- Hidetaka Hara
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Huy Nguyen
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Zheng-Yu Wang
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Abhijit Jagdale
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Mohamed Bikhet
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Takayuki Yamamoto
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hayato Iwase
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | - David K C Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
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38
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Abstract
Pigs represent a potentially attractive model for medical research. Similar body size and physiological patterns of kidney injury that more closely mimic those described in humans make larger animals attractive for experimentation. Using larger animals, including pigs, to investigate the pathogenesis of acute kidney injury (AKI) also serves as an experimental bridge, narrowing the gap between clinical disease and preclinical discoveries. This article compares the advantages and disadvantages of large versus small AKI animal models and provides a comprehensive overview of the development and application of porcine models of AKI induced by clinically relevant insults, including ischemia-reperfusion, sepsis, and nephrotoxin exposure. The primary focus of this review is to evaluate the use of pigs for AKI studies by current investigators, including areas where more information is needed.
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Affiliation(s)
- Jianni Huang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - George Bayliss
- Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island
| | - Shougang Zhuang
- Department of Nephrology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.,Department of Medicine, Rhode Island Hospital and Alpert Medical School, Brown University, Providence, Rhode Island
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39
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Meier RPH, Longchamp A, Mohiuddin M, Manuel O, Vrakas G, Maluf DG, Buhler LH, Muller YD, Pascual M. Recent progress and remaining hurdles toward clinical xenotransplantation. Xenotransplantation 2021; 28:e12681. [PMID: 33759229 DOI: 10.1111/xen.12681] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 02/12/2021] [Accepted: 02/21/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Xenotransplantation has made tremendous progress over the last decade. METHODS We discuss kidney and heart xenotransplantation, which are nearing initial clinical trials. RESULTS Life sustaining genetically modified kidney xenografts can now last for approximately 500 days and orthotopic heart xenografts for 200 days in non-human primates. Anti-swine specific antibody screening, preemptive desensitization protocols, complement inhibition and targeted immunosuppression are currently being adapted to xenotransplantation with the hope to achieve better control of antibody-mediated rejection (AMR) and improve xenograft longevity. These newest advances could probably facilitate future clinical trials, a significant step for the medical community, given that dialysis remains difficult for many patients and can have prohibitive costs. Performing a successful pig-to-human clinical kidney xenograft, that could last for more than a year after transplant, seems feasible but it still has significant potential hurdles to overcome. The risk/benefit balance is progressively reaching an acceptable equilibrium for future human recipients, e.g. those with a life expectancy inferior to two years. The ultimate question at this stage would be to determine if a "proof of concept" in humans is desirable, or whether further experimental/pre-clinical advances are still needed to demonstrate longer xenograft survival in non-human primates. CONCLUSION In this review, we discuss the most recent advances in kidney and heart xenotransplantation, with a focus on the prevention and treatment of AMR and on the recipient's selection, two aspects that will likely be the major points of discussion in the first pig organ xenotransplantation clinical trials.
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Affiliation(s)
- Raphael P H Meier
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Alban Longchamp
- Department of Vascular Surgery, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Muhammad Mohiuddin
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Oriol Manuel
- Transplantation Center, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
| | - Georgios Vrakas
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Daniel G Maluf
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Leo H Buhler
- Faculty of Science and Medicine, Section of Medicine, University of Fribourg, Fribourg, Switzerland
| | - Yannick D Muller
- Division of Immunology and Allergy, University Hospital of Lausanne, Lausanne, Switzerland
| | - Manuel Pascual
- Transplantation Center, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland
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40
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Wang SY, Zhang CY, Cai GY, Chen XM. Method used to establish a large animal model of drug-induced acute kidney injury. Exp Biol Med (Maywood) 2021; 246:986-995. [PMID: 33467911 DOI: 10.1177/1535370220981756] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Acute kidney injury is a serious health hazard disease due to its complex etiology and lack of effective treatments, resulting in high medical costs and high mortality. At present, a large number of basic research studies on acute kidney injury have been carried out. However, acute kidney injury models established in rodents sometimes do not simulate the course of human disease well. Research in large animal models of acute kidney injury is relatively rare, and methods to build a mature model of acute kidney injury have failed. Because its kidney anatomy and morphology are very similar to those in humans, the mini pig is an ideal animal in which to model kidney disease. Nephrotoxic drug-induced acute kidney injury has a high incidence. In this study, we established models of acute kidney injury induced by two drugs (gentamicin and cisplatin). Finally, the model of cisplatin-induced acute kidney injury was developed successfully, but we found the model of gentamycin-induced acute kidney injury was not reproducible. Compared to other models, these models better represent acute kidney injury caused by antibiotics and chemotherapeutic drugs and provide a basis for the study of new treatments for acute kidney injury in a large animal model.
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Affiliation(s)
- Si-Yang Wang
- Department of Nephrology, the First Medical Centre, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China
- 953th Hospital, Shigatse Branch, Xinqiao Hospital, Army Medical University (Third Military Medical University), Shigatse 857000, China
| | - Chao-Yang Zhang
- Department of Nephrology, the First Medical Centre, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China
| | - Guang-Yan Cai
- Department of Nephrology, the First Medical Centre, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China
| | - Xiang-Mei Chen
- Department of Nephrology, the First Medical Centre, Chinese PLA General Hospital, Chinese PLA Institute of Nephrology, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing 100853, China
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Yu XH, Deng WY, Jiang HT, Li T, Wang Y. Kidney xenotransplantation: Recent progress in preclinical research. Clin Chim Acta 2020; 514:15-23. [PMID: 33301767 DOI: 10.1016/j.cca.2020.11.028] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 11/26/2020] [Accepted: 11/30/2020] [Indexed: 01/23/2023]
Abstract
Kidney transplantation is the most effective treatment for end-stage renal disease, but is limited by the increasing shortage of deceased and living human donor kidneys. Xenotransplantation using pig organs provides the possibility to resolve the issue of organ supply shortage and is regarded as the next great medical revolution. In the past five years, there have been sequential advances toward the prolongation of life-supporting pig kidney xenograft survival in non-human primates, with the longest survival being 499 days. This progress is due to the growing availability of pigs with multi-layered genetic modifications to overcome the pathobiological barriers and the application of a costimulation blockade-based immunosuppressive regimen. These encouraging results bring the hope to initiate the clinical trials of pig kidney transplantation in the near future. In this review, we summarized the latest advances regarding pig kidney xenotransplantation in preclinical models to provide a basis for future investigation and potential clinical translation.
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Affiliation(s)
- Xiao-Hua Yu
- Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 460106, China; The Transplantation Institute of Hainan Medical University, Haikou, Hainan 460106, China
| | - Wen-Yi Deng
- Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 460106, China; The Transplantation Institute of Hainan Medical University, Haikou, Hainan 460106, China
| | - Hong-Tao Jiang
- Department of Organ Transplantation, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 460106, China; The Transplantation Institute of Hainan Medical University, Haikou, Hainan 460106, China
| | - Tao Li
- Department of Organ Transplantation, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 460106, China; The Transplantation Institute of Hainan Medical University, Haikou, Hainan 460106, China
| | - Yi Wang
- Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 460106, China; Department of Organ Transplantation, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 460106, China; The Transplantation Institute of Hainan Medical University, Haikou, Hainan 460106, China.
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Iwase H, Ball S, Adams K, Eyestone W, Walters A, Cooper DKC. Growth hormone receptor knockout: Relevance to xenotransplantation. Xenotransplantation 2020; 28:e12652. [PMID: 33058285 DOI: 10.1111/xen.12652] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 09/03/2020] [Accepted: 09/15/2020] [Indexed: 02/06/2023]
Abstract
Xenotransplantation research has made considerable progress in recent years, largely through the increasing availability of pigs with multiple genetic modifications, effective immunosuppressive therapy, and anti-inflammatory therapy to protect pig tissues from the primate immune and inflammatory responses and correct molecular incompatibilities. Further study is required regarding identification and investigation of physiological incompatibilities. Although the exact cause remains uncertain, we and others have observed relatively rapid growth of kidney xenografts after transplantation into nonhuman primates (NHPs). There has also been some evidence of growth, or at least ventricular hypertrophy, of the pig heart after orthotopic transplantation into NHPs. Rapid growth could be problematic, particularly with regard to the heart within the relatively restricted confines of the chest. It has been suggested that the problem of rapid growth of the pig organ after transplantation could be resolved by growth hormone receptor (GHR) gene knockout in the pig. The GHR, although most well-known for regulating growth, has many other biological functions, including regulating metabolism and controlling physiological processes. Genetically modified GHRKO pigs have recently become available. We provide data on their growth compared to comparable pigs that do not include GHRKO, and we have reviewed the literature regarding the effect of GHRKO, and its relevance to xenotransplantation.
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Affiliation(s)
- Hayato Iwase
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
| | | | | | | | | | - David K C Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
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Cui Y, Yamamoto T, Raza SS, Morsi M, Nguyen HQ, Ayares D, Cooper DK, Hara H. Evidence for GTKO/β4GalNT2KO Pigs as the Preferred Organ-source for Old World Nonhuman Primates as a Preclinical Model of Xenotransplantation. Transplant Direct 2020; 6:e590. [PMID: 32766438 PMCID: PMC7382549 DOI: 10.1097/txd.0000000000001038] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/15/2020] [Accepted: 06/17/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Triple-knockout (TKO) pigs (in which expression of the 3 known pig carbohydrate xenoantigens has been deleted) are likely to be an optimal source of organs for transplantation into human recipients, many of whom do not have natural antibodies against TKO pig cells. However, old world monkeys, for example, baboons, have natural antibodies directed to TKO cells (to a "fourth" xenoantigen that is exposed after TKO). METHODS We measured (1) anti-pig IgM/IgG binding, and (2) complement-dependent cytotoxicity (CDC), by flow cytometry to α1,3-galactosyltransfearse gene-knockout (GTKO), GTKO/β4GalNT2KO (that do not express the "fourth" xenoantigen), and TKO pig peripheral blood mononuclear cells (PBMCs) using 72 baboon sera (30 specific pathogen-free [SPF], and 42 non-SPF baboons). RESULTS Mean IgM antibody binding to GTKO/β4GalNT2KO pig PBMCs was significantly lower than to GTKO or TKO pig PBMCs (P < 0.01). Mean IgG antibody binding to GTKO/β4GalNT2KO pig PBMCs was significantly lower than to TKO PBMCs (P < 0.01). Mean CDC of GTKO/β4GalNT2KO pig PBMCs was significantly lower than of GTKO or TKO pig PBMCs (P < 0.01). SPF baboon serum IgM and IgG binding to, and CDC of, GTKO/β4GalNT2KO or TKO PBMCs were significantly lower than non-SPF baboon sera (P < 0.01). CONCLUSIONS Although TKO pigs form the basis for proposed clinical trials of xenotransplantation, it is difficult to identify baboons with a low or negative CDC to TKO pigs. For pig-to-baboon organ transplantation, the use of GTKO/β4GalNT2KO pigs would be preferable. The use of SPF baboons as recipients might be a minor advantage.
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Affiliation(s)
- Yehua Cui
- Department of Urology, Second Affiliated Hospital, University of South China, Hengyang City, Hunan, China
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Takayuki Yamamoto
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Syed Sikandar Raza
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Mahmoud Morsi
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Huy Quoc Nguyen
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | | | - David K.C. Cooper
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
| | - Hidetaka Hara
- Xenotransplantation Program, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL
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