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Tsai IT, Sun CK. Stem Cell Therapy against Ischemic Heart Disease. Int J Mol Sci 2024; 25:3778. [PMID: 38612587 PMCID: PMC11011361 DOI: 10.3390/ijms25073778] [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: 02/07/2024] [Revised: 03/12/2024] [Accepted: 03/26/2024] [Indexed: 04/14/2024] Open
Abstract
Ischemic heart disease, which is one of the top killers worldwide, encompasses a series of heart problems stemming from a compromised coronary blood supply to the myocardium. The severity of the disease ranges from an unstable manifestation of ischemic symptoms, such as unstable angina, to myocardial death, that is, the immediate life-threatening condition of myocardial infarction. Even though patients may survive myocardial infarction, the resulting ischemia-reperfusion injury triggers a cascade of inflammatory reactions and oxidative stress that poses a significant threat to myocardial function following successful revascularization. Moreover, despite evidence suggesting the presence of cardiac stem cells, the fact that cardiomyocytes are terminally differentiated and cannot significantly regenerate after injury accounts for the subsequent progression to ischemic cardiomyopathy and ischemic heart failure, despite the current advancements in cardiac medicine. In the last two decades, researchers have realized the possibility of utilizing stem cell plasticity for therapeutic purposes. Indeed, stem cells of different origin, such as bone-marrow- and adipose-derived mesenchymal stem cells, circulation-derived progenitor cells, and induced pluripotent stem cells, have all been shown to play therapeutic roles in ischemic heart disease. In addition, the discovery of stem-cell-associated paracrine effects has triggered intense investigations into the actions of exosomes. Notwithstanding the seemingly promising outcomes from both experimental and clinical studies regarding the therapeutic use of stem cells against ischemic heart disease, positive results from fraud or false data interpretation need to be taken into consideration. The current review is aimed at overviewing the therapeutic application of stem cells in different categories of ischemic heart disease, including relevant experimental and clinical outcomes, as well as the proposed mechanisms underpinning such observations.
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Affiliation(s)
- I-Ting Tsai
- Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung City 82445, Taiwan;
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung City 82445, Taiwan
| | - Cheuk-Kwan Sun
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung City 82445, Taiwan
- Department of Emergency Medicine, E-Da Dachang Hospital, I-Shou University, Kaohsiung City 80794, Taiwan
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Efficacy of Stem Cell Therapy in Large Animal Models of Ischemic Cardiomyopathies: A Systematic Review and Meta-Analysis. Animals (Basel) 2022; 12:ani12060749. [PMID: 35327146 PMCID: PMC8944644 DOI: 10.3390/ani12060749] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 03/09/2022] [Accepted: 03/14/2022] [Indexed: 12/13/2022] Open
Abstract
Stem-cell therapy provides a promising strategy for patients with ischemic heart disease. In recent years, numerous studies related to this therapeutic approach were performed; however, the results were often heterogeneous and contradictory. For this reason, we conducted a systematic review and meta-analysis of trials, reporting the use of stem-cell treatment against acute or chronic ischemic cardiomyopathies in large animal models with regard to Left Ventricular Ejection Fraction (LVEF). The defined research strategy was applied to the PubMed database to identify relevant studies published from January 2011 to July 2021. A random-effect meta-analysis was performed on LVEF mean data at follow-up between control and stem-cell-treated animals. In order to improve the definition of the effect measure and to analyze the factors that could influence the outcomes, a subgroup comparison was conducted. Sixty-six studies (n = 1183 animals) satisfied our inclusion criteria. Ischemia/reperfusion infarction was performed in 37 studies, and chronic occlusion in 29 studies; moreover, 58 studies were on a pig animal model. The meta-analysis showed that cell therapy increased LVEF by 7.41% (95% Confidence Interval 6.23−8.59%; p < 0.001) at follow-up, with significative heterogeneity and high inconsistency (I2 = 82%, p < 0.001). By subgroup comparison, the follow-up after 31−60 days (p = 0.025), the late cell injection (>7 days, p = 0.005) and the route of cellular delivery by surgical treatment (p < 0.001) were significant predictors of LVEF improvement. This meta-analysis showed that stem-cell therapy may improve heart function in large animal models and that the swine specie is confirmed as a relevant animal model in the cardiovascular field. Due to the significative heterogeneity and high inconsistency, future translational studies should be designed to take into account the evidenced predictors to allow for the reduction of the number of animals used.
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Furia JP, Lundeen MA, Hurd JL, Pearce DA, Alt C, Alt EU, Schmitz C, Maffulli N. Why and how to use the body's own stem cells for regeneration in musculoskeletal disorders: a primer. J Orthop Surg Res 2022; 17:36. [PMID: 35062984 PMCID: PMC8781360 DOI: 10.1186/s13018-022-02918-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Accepted: 01/03/2022] [Indexed: 12/25/2022] Open
Abstract
Abstract
Background
Recently, the management of musculoskeletal disorders with the patients' own stem cells, isolated from the walls of small blood vessels, which can be found in great numbers in the adipose tissue, has received considerable attention. On the other hand, there are still misconceptions about these adipose-derived regenerative cells (ADRCs) that contain vascular-associated pluripotent stem cells (vaPS cells) in regenerative medicine.
Methods
Based on our previous publications on this topic, we have developed a concept to describe the significance of the ADRCs/vaPS cells in the field of orthobiologics as briefly as possible and at the same time as precisely as possible.
Results
The ADRCs/vaPS cells belong to the group of orthobiologics that are based on autologous cells. Because the latter can both stimulate a patient’s body's localized self-healing power and provide new cells that can integrate into the host tissue during the healing response when the localized self-healing power is exhausted, this group of orthobiologics appears more advantageous than cell-free orthobiologics and orthobiologics that are based on allogeneic cells. Within the group of orthobiologics that are based on autologous cells, enzymatically isolated, uncultured ADRCs/vaPS cells have several advantages over non-enzymatically isolated cells/microfragmented fat as well as over uncultured bone marrow aspirate concentrate and cultured cells (adipose-derived stem cells, bone marrow-derived mesenchymal stem cells).
Conclusions
The use of ADRCs/vaPS cells can be seamlessly integrated into modern orthopedic treatment concepts, which can be understood as the optimization of a process which—albeit less efficiently—also takes place physiologically. Accordingly, this new safe and effective type of treatment is attractive in terms of holistic thinking and personalized medicine.
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Alt EU, Schmitz C, Bai X. Perspective: Why and How Ubiquitously Distributed, Vascular-Associated, Pluripotent Stem Cells in the Adult Body (vaPS Cells) Are the Next Generation of Medicine. Cells 2021; 10:2303. [PMID: 34571951 PMCID: PMC8467324 DOI: 10.3390/cells10092303] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 08/30/2021] [Accepted: 08/31/2021] [Indexed: 12/21/2022] Open
Abstract
A certain cell type can be isolated from different organs in the adult body that can differentiate into ectoderm, mesoderm, and endoderm, providing significant support for the existence of a certain type of small, vascular-associated, pluripotent stem cell ubiquitously distributed in all organs in the adult body (vaPS cells). These vaPS cells fundamentally differ from embryonic stem cells and induced pluripotent stem cells in that the latter possess the necessary genetic guidance that makes them intrinsically pluripotent. In contrast, vaPS cells do not have this intrinsic genetic guidance, but are able to differentiate into somatic cells of all three lineages under guidance of the microenvironment they are located in, independent from the original tissue or organ where they had resided. These vaPS cells are of high relevance for clinical application because they are contained in unmodified, autologous, adipose-derived regenerative cells (UA-ADRCs). The latter can be obtained from and re-applied to the same patient at the point of care, without the need for further processing, manipulation, and culturing. These findings as well as various clinical examples presented in this paper demonstrate the potential of UA-ADRCs for enabling an entirely new generation of medicine for the benefit of patients and healthcare systems.
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Affiliation(s)
- Eckhard U. Alt
- Heart and Vascular Institute, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA;
- Sanford School of Medicine, University of South Dakota, Sioux Falls, SD 57104, USA
- MD Anderson Cancer Center, University of Texas, Houston, TX 77054, USA
- Isar Klinikum Munich, 80331 Munich, Germany
| | - Christoph Schmitz
- Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilians University of Munich, 80336 Munich, Germany;
| | - Xiaowen Bai
- Heart and Vascular Institute, Department of Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA;
- MD Anderson Cancer Center, University of Texas, Houston, TX 77054, USA
- Department of Cell Biology, Neurobiology & Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
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Alt E, Rothoerl R, Hoppert M, Frank HG, Wuerfel T, Alt C, Schmitz C. First immunohistochemical evidence of human tendon repair following stem cell injection: A case report and review of literature. World J Stem Cells 2021; 13:944-970. [PMID: 34367486 PMCID: PMC8316863 DOI: 10.4252/wjsc.v13.i7.944] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 04/29/2021] [Accepted: 06/25/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Current clinical treatment options for symptomatic, partial-thickness rotator cuff tear (sPTRCT) offer only limited potential for true tissue healing and improvement of clinical results. In animal models, injections of adult stem cells isolated from adipose tissue into tendon injuries evidenced histological regeneration of tendon tissue. However, it is unclear whether such beneficial effects could also be observed in a human tendon treated with fresh, uncultured, autologous, adipose derived regenerative cells (UA-ADRCs). A specific challenge in this regard is that UA-ADRCs cannot be labeled and, thus, not unequivocally identified in the host tissue. Therefore, histological regeneration of injured human tendons after injection of UA-ADRCs must be assessed using comprehensive, immunohistochemical and microscopic analysis of biopsies taken from the treated tendon a few weeks after injection of UA-ADRCs.
CASE SUMMARY A 66-year-old patient suffered from sPTRCT affecting the right supraspinatus and infraspinatus tendon, caused by a bicycle accident. On day 18 post injury [day 16 post magnetic resonance imaging (MRI) examination] approximately 100 g of abdominal adipose tissue was harvested by liposuction, from which approximately 75 × 106 UA-ADRCs were isolated within 2 h. Then, UA-ADRCs were injected (controlled by biplanar X-ray imaging) adjacent to the injured supraspinatus tendon immediately after isolation. Despite fast clinical recovery, a follow-up MRI examination 2.5 mo post treatment indicated the need for open revision of the injured infraspinatus tendon, which had not been treated with UA-ADRCs. During this operation, a biopsy was taken from the supraspinatus tendon at the position of the injury. A comprehensive, immunohistochemical and microscopic analysis of the biopsy (comprising 13 antibodies) was indicative of newly formed tendon tissue.
CONCLUSION Injection of UA-ADRCs can result in regeneration of injured human tendons by formation of new tendon tissue.
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Affiliation(s)
- Eckhard Alt
- Chairman of the Board, Isarklinikum Munich, Munich 80331, Germany
| | - Ralf Rothoerl
- Department of Spine Surgery, Isarklinikum Munich, Munich 80331, Germany
| | - Matthias Hoppert
- Department for Orthopedics and Trauma Surgery, Isarklinikum Munich, Munich 80331, Germany
| | - Hans-Georg Frank
- Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich 80336, Germany
| | - Tobias Wuerfel
- Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich 80336, Germany
| | - Christopher Alt
- Director of Science and Research, InGeneron GmbH, Munich 80331, Germany
| | - Christoph Schmitz
- Chair of Neuroanatomy, Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich 80336, Germany
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Adipose stem cells in obesity: challenges and opportunities. Biosci Rep 2021; 40:225001. [PMID: 32452515 PMCID: PMC7284323 DOI: 10.1042/bsr20194076] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/08/2020] [Accepted: 05/22/2020] [Indexed: 02/07/2023] Open
Abstract
Adipose tissue, the storage of excessive energy in the body, secretes various proteins called adipokines, which connect the body’s nutritional status to the regulation of energy balance. Obesity triggers alterations of quantity and quality of various types of cells that reside in adipose tissue, including adipose stem cells (ASCs; referred to as adipose-derived stem/stromal cells in vitro). These alterations in the functionalities and properties of ASCs impair adipose tissue remodeling and adipose tissue function, which induces low-grade systemic inflammation, progressive insulin resistance, and other metabolic disorders. In contrast, the ability of ASCs to recruit new adipocytes when faced with caloric excess leads to healthy adipose tissue expansion, associated with lower amounts of inflammation, fibrosis, and insulin resistance. This review focuses on recent advances in our understanding of the identity of ASCs and their roles in adipose tissue development, homeostasis, expansion, and thermogenesis, and how these roles go awry in obesity. A better understanding of the biology of ASCs and their adipogenesis may lead to novel therapeutic targets for obesity and metabolic disease.
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Alt EU, Winnier G, Haenel A, Rothoerl R, Solakoglu O, Alt C, Schmitz C. Towards a Comprehensive Understanding of UA-ADRCs (Uncultured, Autologous, Fresh, Unmodified, Adipose Derived Regenerative Cells, Isolated at Point of Care) in Regenerative Medicine. Cells 2020; 9:E1097. [PMID: 32365488 PMCID: PMC7290808 DOI: 10.3390/cells9051097] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/18/2020] [Accepted: 04/21/2020] [Indexed: 02/06/2023] Open
Abstract
It has become practically impossible to survey the literature on cells derived from adipose tissue for regenerative medicine. The aim of this paper is to provide a comprehensive and translational understanding of the potential of UA-ADRCs (uncultured, unmodified, fresh, autologous adipose derived regenerative cells isolated at the point of care) and its application in regenerative medicine. We provide profound basic and clinical evidence demonstrating that tissue regeneration with UA-ADRCs is safe and effective. ADRCs are neither 'fat stem cells' nor could they exclusively be isolated from adipose tissue. ADRCs contain the same adult stem cells ubiquitously present in the walls of blood vessels that are able to differentiate into cells of all three germ layers. Of note, the specific isolation procedure used has a significant impact on the number and viability of cells and hence on safety and efficacy of UA-ADRCs. Furthermore, there is no need to specifically isolate and separate stem cells from the initial mixture of progenitor and stem cells found in ADRCs. Most importantly, UA-ADRCs have the physiological capacity to adequately regenerate tissue without need for more than minimally manipulating, stimulating and/or (genetically) reprogramming the cells for a broad range of clinical applications. Tissue regeneration with UA-ADRCs fulfills the criteria of homologous use as defined by the regulatory authorities.
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Affiliation(s)
- Eckhard U. Alt
- Heart and Vascular Institute, Department of Medicine, Tulane University Health Science Center, New Orleans, LA 70112, USA
- Sanford Health, University of South Dakota, Sioux Falls, SD 57104, USA
- University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA
- Isar Klinikum Munich, 80331 Munich, Germany
- InGeneron, Inc., Houston, TX 77054, USA
| | | | - Alexander Haenel
- Heart and Vascular Institute, Department of Medicine, Tulane University Health Science Center, New Orleans, LA 70112, USA
- Department of Radiology and Nuclear Medicine, University Hospital Schleswig-Holstein, 23562 Lübeck, Germany
| | | | - Oender Solakoglu
- Dental Department of the University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
- Periodontology and Implant Dentistry, 22453 Hamburg, Germany
| | | | - Christoph Schmitz
- Institute of Anatomy, Faculty of Medicine, LMU Munich, 80331 Munich, Germany
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Hurd JL, Facile TR, Weiss J, Hayes M, Hayes M, Furia JP, Maffulli N, Winnier GE, Alt C, Schmitz C, Alt EU, Lundeen M. Safety and efficacy of treating symptomatic, partial-thickness rotator cuff tears with fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) isolated at the point of care: a prospective, randomized, controlled first-in-human pilot study. J Orthop Surg Res 2020; 15:122. [PMID: 32238172 PMCID: PMC7110715 DOI: 10.1186/s13018-020-01631-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 03/12/2020] [Indexed: 02/07/2023] Open
Abstract
Background This study tested the hypothesis that treatment of symptomatic, partial-thickness rotator cuff tears (sPTRCT) with fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) isolated from lipoaspirate at the point of care is safe and more effective than corticosteroid injection. Methods Subjects aged between 30 and 75 years with sPTRCT who did not respond to physical therapy treatments for at least 6 weeks were randomly assigned to receive a single injection of an average 11.4 × 106 UA-ADRCs (in 5 mL liquid; mean cell viability: 88%) (n = 11; modified intention-to-treat (mITT) population) or a single injection of 80 mg of methylprednisolone (40 mg/mL; 2 mL) plus 3 mL of 0.25% bupivacaine (n = 5; mITT population), respectively. Safety and efficacy were assessed using the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES), RAND Short Form-36 Health Survey, and pain visual analogue scale (VAS) at baseline (BL) as well as 3 weeks (W3), W6, W9, W12, W24, W32, W40, and W52 post treatment. Fat-saturated T2-weighted magnetic resonance imaging of the shoulder was performed at BL as well as at W24 and W52 post treatment. Results No severe adverse events related to the injection of UA-ADRCs were observed in the 12 months post treatment. The risks connected with treatment of sPTRCT with UA-ADRCs were not greater than those connected with treatment of sPTRCT with corticosteroid injection. However, one subject in the corticosteroid group developed a full rotator cuff tear during the course of this pilot study. Despite the small number of subjects in this pilot study, those in the UA-ADRCs group showed statistically significantly higher mean ASES total scores at W24 and W52 post treatment than those in the corticosteroid group (p < 0.05). Discussion This pilot study suggests that the use of UA-ADRCs in subjects with sPTRCT is safe and leads to improved shoulder function without adverse effects. To verify the results of this initial safety and feasibility pilot study in a larger patient population, a randomized controlled trial on 246 patients suffering from sPTRCT is currently ongoing. Trial registration Clinicaltrials.gov ID NCT02918136. Registered September 28, 2016, https://clinicaltrials.gov/ct2/show/NCT02918136. Level of evidence Level I; prospective, randomized, controlled trial.
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Affiliation(s)
- Jason L Hurd
- Sanford Orthopedics & Sports Medicine Sioux Falls, 1210 W. 18th St., Suite G01, Sioux Falls, SD, 57104, USA.
| | | | | | | | | | - John P Furia
- SUN Orthopedics of Evangelical Community Hospital, Lewisburg, PA, USA
| | - Nicola Maffulli
- Department of Musculoskeletal Disorders, Faculty of Medicine and Surgery, University of Salerno, Salerno, Italy.,Centre for Sports and Exercise Medicine, Barts and The London School of Medicine and Dentistry, Mile End Hospital, Queen Mary University of London, London, UK.,School of Pharmacy and Bioengineering, Guy Hilton Research Centre, Keele University School of Medicine, Stoke on Trent, UK
| | | | | | - Christoph Schmitz
- Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Eckhard U Alt
- Sanford Health, Sioux Falls, SD, USA.,InGeneron, Inc., Houston, TX, USA.,Isar Klinikum, Munich, Germany
| | - Mark Lundeen
- Sanford Orthopedics & Sports Medicine Fargo, Fargo, ND, USA
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