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Bukowska J, Szóstek-Mioduchowska AZ, Kopcewicz M, Walendzik K, Machcińska S, Gawrońska-Kozak B. Adipose-Derived Stromal/Stem Cells from Large Animal Models: from Basic to Applied Science. Stem Cell Rev Rep 2020; 17:719-738. [PMID: 33025392 PMCID: PMC8166671 DOI: 10.1007/s12015-020-10049-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2020] [Indexed: 12/16/2022]
Abstract
Adipose-derived stem cells (ASCs) isolated from domestic animals fulfill the qualitative criteria of mesenchymal stem cells, including the capacity to differentiate along multiple lineage pathways and to self-renew, as well as immunomodulatory capacities. Recent findings on human diseases derived from studying large animal models, have provided evidence that administration of autologous or allogenic ASCs can improve the process of healing. In a narrow group of large animals used in bioresearch studies, pigs and horses have been shown to be the best suited models for study of the wound healing process, cardiovascular and musculoskeletal disorders. To this end, current literature demonstrates that ASC-based therapies bring considerable benefits to animal health in both spontaneously occurring and experimentally induced clinical cases. The purpose of this review is to provide an overview of the diversity, isolation, and characterization of ASCs from livestock. Particular attention has been paid to the functional characteristics of the cells that facilitate their therapeutic application in large animal models of human disease. In this regard, we describe outcomes of ASCs utilization in translational research with pig and horse models of disease. Furthermore, we evaluate the current status of ASC-based therapy in veterinary practice, particularly in the rapidly developing field of equine regenerative medicine. In conclusion, this review presents arguments that support the relevance of animal ASCs in the field of regenerative medicine and it provides insights into the future perspectives of ASC utilization in animal husbandry.
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Affiliation(s)
- Joanna Bukowska
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10, 10-748, Olsztyn, Poland.
| | | | - Marta Kopcewicz
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10, 10-748, Olsztyn, Poland
| | - Katarzyna Walendzik
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10, 10-748, Olsztyn, Poland
| | - Sylwia Machcińska
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10, 10-748, Olsztyn, Poland
| | - Barbara Gawrońska-Kozak
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10, 10-748, Olsztyn, Poland
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Haenel A, Ghosn M, Karimi T, Vykoukal J, Shah D, Valderrabano M, Schulz DG, Raizner A, Schmitz C, Alt EU. Unmodified autologous stem cells at point of care for chronic myocardial infarction. World J Stem Cells 2019; 11:831-858. [PMID: 31692971 PMCID: PMC6828597 DOI: 10.4252/wjsc.v11.i10.831] [Citation(s) in RCA: 8] [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: 02/18/2019] [Revised: 06/03/2019] [Accepted: 08/27/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Numerous studies investigated cell-based therapies for myocardial infarction (MI). The conflicting results of these studies have established the need for developing innovative approaches for applying cell-based therapy for MI. Experimental studies on animal models demonstrated the potential of fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) for treating acute MI. In contrast, studies on the treatment of chronic MI (CMI; > 4 wk post-MI) with UA-ADRCs have not been published so far. Among several methods for delivering cells to the myocardium, retrograde delivery into a temporarily blocked coronary vein has recently been demonstrated as an effective option.
AIM To test the hypothesis that in experimentally-induced chronic myocardial infarction (CMI; > 4 wk post-MI) in pigs, retrograde delivery of fresh, uncultured, unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) into a temporarily blocked coronary vein improves cardiac function and structure.
METHODS The left anterior descending (LAD) coronary artery of pigs was blocked for 180 min at time point T0. Then, either 18 × 106 UA-ADRCs prepared at “point of care” or saline as control were retrogradely delivered via an over-the-wire balloon catheter placed in the temporarily blocked LAD vein 4 wk after T0 (T1). Effects of cells or saline were assessed by cardiac magnetic resonance (CMR) imaging, late gadolinium enhancement CMR imaging, and post mortem histologic analysis 10 wk after T0 (T2).
RESULTS Unlike the delivery of saline, delivery of UA-ADRCs demonstrated statistically significant improvements in cardiac function and structure at T2 compared to T1 (all values given as mean ± SE): Increased mean LVEF (UA-ADRCs group: 34.3% ± 2.9% at T1 vs 40.4 ± 2.6% at T2, P = 0.037; saline group: 37.8% ± 2.6% at T1 vs 36.2% ± 2.4% at T2, P > 0.999), increased mean cardiac output (UA-ADRCs group: 2.7 ± 0.2 L/min at T1 vs 3.8 ± 0.2 L/min at T2, P = 0.002; saline group: 3.4 ± 0.3 L/min at T1 vs 3.6 ± 0.3 L/min at T2, P = 0.798), increased mean mass of the left ventricle (UA-ADRCs group: 55.3 ± 5.0 g at T1 vs 71.3 ± 4.5 g at T2, P < 0.001; saline group: 63.2 ± 3.4 g at T1 vs 68.4 ± 4.0 g at T2, P = 0.321) and reduced mean relative amount of scar volume of the left ventricular wall (UA-ADRCs group: 20.9% ± 2.3% at T1 vs 16.6% ± 1.2% at T2, P = 0.042; saline group: 17.6% ± 1.4% at T1 vs 22.7% ± 1.8% at T2, P = 0.022).
CONCLUSION Retrograde cell delivery of UA-ADRCs in a porcine model for the study of CMI significantly improved myocardial function, increased myocardial mass and reduced the formation of scar tissue.
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Affiliation(s)
- Alexander Haenel
- Heart and Vascular Institute, Department of Medicine, Tulane University Health Science Center, New Orleans, LA 70112, United States
- The Methodist Hospital Research Institute, Houston, TX 77030, United States
- Department of Radiology and Nuclear Medicine, University Hospital Schleswig-Holstein, Lübeck D-23562, Germany
| | - Mohamad Ghosn
- Houston Methodist DeBakey Heart and Vascular Center, Houston, TX 77030, United States
| | - Tahereh Karimi
- Heart and Vascular Institute, Department of Medicine, Tulane University Health Science Center, New Orleans, LA 70112, United States
| | - Jody Vykoukal
- Department of Translational Molecular Pathology, MD Anderson Cancer Center, The University of Texas, Houston, TX 77030, United States
| | - Dipan Shah
- Houston Methodist DeBakey Heart and Vascular Center, Houston, TX 77030, United States
| | - Miguel Valderrabano
- Houston Methodist DeBakey Heart and Vascular Center, Houston, TX 77030, United States
| | - Daryl G Schulz
- The Methodist Hospital Research Institute, Houston, TX 77030, United States
| | - Albert Raizner
- Houston Methodist DeBakey Heart and Vascular Center, Houston, TX 77030, United States
| | - Christoph Schmitz
- Institute of Anatomy, Faculty of Medicine, LMU Munich, Munich D-80336, Germany
| | - Eckhard U Alt
- Heart and Vascular Institute, Department of Medicine, Tulane University Health Science Center, New Orleans, LA 70112, United States
- The Methodist Hospital Research Institute, Houston, TX 77030, United States
- Isar Klinikum Munich, Munich D-80331, Germany
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Kolettis TM, Bagli E, Barka E, Kouroupis D, Kontonika M, Vilaeti AD, Markou M, Roumpi M, Maltabe V, La Rocca V, Agathopoulos S, Fotsis T. Medium-term Electrophysiologic Effects of a Cellularized Scaffold Implanted in Rats After Myocardial Infarction. Cureus 2018; 10:e2959. [PMID: 30214847 PMCID: PMC6132679 DOI: 10.7759/cureus.2959] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Background Cardiac repair strategies are being evaluated for myocardial infarctions, but the safety issues regarding their arrhythmogenic potential remain unresolved. By utilizing the in-vivo rat model, we have examined the medium-term electrophysiologic effects of a biomaterial scaffold that has been cellularized with spheroids of human adipose tissue, derived from mesenchymal stem cells and umbilical vein endothelial cells. Methods Mesenchymal stem cells, which exhibit adequate differentiation capacity, were co-cultured with umbilical vein endothelial cells and were seeded on an alginate based scaffold. After in-vitro characterization, the cellularized scaffold was implanted in (n=15) adult Wistar rats 15 min post ligation of the left coronary artery, with an equal number of animals serving as controls. Two weeks thereafter, monophasic action potentials were recorded and activation-mapping was performed with a multi-electrode array. An arrhythmia score for inducible ventricular tachyarrhythmias was calculated after programmed electrical stimulation. Results The arrhythmia score was comparable between the treated animals and controls. No differences were detected in the local conduction at the infarct border and in the voltage rise in monophasic action potential recordings. Treatment did not affect the duration of local repolarization, but tended to enhance its dispersion. Conclusions The fabricated bi-culture cellularized scaffold displayed favorable properties after in-vitro characterization. Medium-term electrophysiologic assessment after implantation in the infarcted rat myocardium revealed low arrhythmogenic potential, but the long-term effects on repolarization dispersion will require further investigation.
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Affiliation(s)
| | - Eleni Bagli
- Division of Biomedical Research, Institute of Molecular Biology and Biotechnology - Forth, Ioannina, GRC
| | - Eleonora Barka
- Ceramics and Composites Laboratory, Materials Science and Engineering, University of Ioannina, Ioannina, GRC
| | - Dimitrios Kouroupis
- Division of Biomedical Research, Institute of Molecular Biology and Biotechnology - Forth, Ioannina, GRC
| | | | | | - Maria Markou
- Division of Biomedical Research, Institute of Molecular Biology and Biotechnology - Forth, Ioannina, GRC
| | - Maria Roumpi
- Ceramics and Composites Laboratory, Science and Engineering, University of Ioannina, Ioannina, GRC
| | - Violetta Maltabe
- Division of Biomedical Research, Institute of Molecular Biology and Biotechnology - Forth, Ioannina, GRC
| | | | - Simeon Agathopoulos
- Ceramics and Composites Laboratory, Materials Science and Engineering, University of Ioannina, Ioannina, GRC
| | - Theodore Fotsis
- Division of Biomedical Research, Institute of Molecular Biology and Biotechnology - Forth, Ioannina, GRC
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Adipose-derived Mesenchymal Stem Cells and Their Reparative Potential in Ischemic Heart Disease. ACTA ACUST UNITED AC 2015; 68:599-611. [DOI: 10.1016/j.rec.2015.02.025] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 02/23/2015] [Indexed: 12/21/2022]
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Badimon L, Oñate B, Vilahur G. Células madre mesenquimales derivadas de tejido adiposo y su potencial reparador en la enfermedad isquémica coronaria. Rev Esp Cardiol 2015. [DOI: 10.1016/j.recesp.2015.02.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Minteer DM, Marra KG, Rubin JP. Adipose stem cells: biology, safety, regulation, and regenerative potential. Clin Plast Surg 2015; 42:169-79. [PMID: 25827561 DOI: 10.1016/j.cps.2014.12.007] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
This article discusses adipose-derived stem cell (ASC) biology, describes the current knowledge in the literature for the safety and regulation of ASCs, and provides a brief overview of the regenerative potential of ASCs. It is not an exhaustive listing of all available clinical studies or every study applying ASCs in tissue engineering and regenerative medicine, but is an objective commentary of these topics.
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Affiliation(s)
- Danielle M Minteer
- Department of Bioengineering, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA
| | - Kacey G Marra
- Department of Bioengineering, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA; Department of Plastic Surgery, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15213, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Pittsburgh, PA 15213, USA
| | - J Peter Rubin
- Department of Bioengineering, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA; Department of Plastic Surgery, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15213, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, 450 Technology Drive, Pittsburgh, PA 15213, USA.
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Adipose-Derived Stem Cells for Therapeutic Applications. Regen Med 2015. [DOI: 10.1007/978-1-4471-6542-2_9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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Hong SJ, Hou D, Brinton TJ, Johnstone B, Feng D, Rogers P, Fearon WF, Yock P, March KL. Intracoronary and retrograde coronary venous myocardial delivery of adipose-derived stem cells in swine infarction lead to transient myocardial trapping with predominant pulmonary redistribution. Catheter Cardiovasc Interv 2013; 83:E17-25. [PMID: 22972685 DOI: 10.1002/ccd.24659] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2012] [Accepted: 09/09/2012] [Indexed: 01/31/2023]
Abstract
OBJECTIVES To examine the comparative fate of adipose-derived stem cells (ASCs) as well as their impact on coronary microcirculation following either retrograde coronary venous (RCV) or arterial delivery. BACKGROUND Local delivery of ASCs to the heart has been proposed as a practical approach to limiting the extent of myocardial infarction. Mouse models of mesenchymal stem cell effects on the heart have also demonstrated significant benefits from systemic (intravenous) delivery, prompting a question about the advantage of local delivery. There has been no study addressing the extent of myocardial vs. systemic disposition of ASCs in large animal models following local delivery to the myocardium. METHODS In an initial experiment, dose-dependent effects of ASC delivery on coronary circulation in normal swine were evaluated to establish a tolerable ASC dosing range for intracoronary (IC) delivery. In a set of subsequent experiments, an anterior acute myocardial infarction (AMI) was created by balloon occlusion of the proximal left anterior descending (LAD) artery, followed by either IC or RCV infusion of 10(7) (111)Indium-labeled autologous ASCs 6 days following AMI. Indices of microcirculatory resistance (IMR) and coronary flow reserve (CFR) were measured before sacrifices to collect tissues for analysis at 1 or 24 hr after cell delivery. RESULTS IC delivery of porcine ASCs to normal myocardium was well tolerated up to a cumulative dose of 14 × 10(6) cells (approximately 0.5 × 10(6) cells/kg). There was evidence suggesting microcirculatory trapping of ASC: at unit doses of 50 × 10(6) ASCs, IMR and CFR were found to be persistently altered in the target LAD distribution at 7 days following delivery, whereas at 10 × 10(6) ASCs, only CFR was altered. In the context of recent MI, a significantly higher percentage of ASCs was retained at 1 hr with IC delivery compared with RCV delivery (57.2 ± 12.7% vs. 17.9 ± 1.6%, P = 0.037) but this initial difference was not apparent at 24 hr (22.6 ± 5.5% vs. 18.7 ± 8.6%; P = 0.722). In both approaches, most ASC redistributed to the pulmonary circulation by 24 hr postdelivery. There were no significant differences in CFR or IMR following ASC delivery to infarcted tissue by either route. CONCLUSIONS Selective intravascular delivery of ASC by coronary arterial and venous routes leads to similarly limited myocardial cell retention with predominant redistribution of cells to the lungs. IC arterial delivery of ASC leads to only transiently greater myocardial retention, which is accompanied by obstruction of normal regions of coronary microcirculation at higher doses. The predominant intrapulmonary localization of cells following local delivery via both methods prompts the notion that systemic delivery of ASC might provide similarly beneficial outcomes while avoiding risks of inadvertent microcirculatory compromise.
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Affiliation(s)
- Soon Jun Hong
- Krannert Institute of Cardiology, Indianapolis; Indiana Center for Vascular Biology and Medicine, Indianapolis; Indiana University School of Medicine, Indianapolis, Indianapolis; Korea University Anam Hospital, Seoul, Korea
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Abstract
In 2001, researchers at the University of California, Los Angeles, described the isolation of a new population of adult stem cells from liposuctioned adipose tissue. These stem cells, now known as adipose-derived stem cells or ADSCs, have gone on to become one of the most popular adult stem cells populations in the fields of stem cell research and regenerative medicine. As of today, thousands of research and clinical articles have been published using ASCs, describing their possible pluripotency in vitro, their uses in regenerative animal models, and their application to the clinic. This paper outlines the progress made in the ASC field since their initial description in 2001, describing their mesodermal, ectodermal, and endodermal potentials both in vitro and in vivo, their use in mediating inflammation and vascularization during tissue regeneration, and their potential for reprogramming into induced pluripotent cells.
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Gimble JM, Bunnell BA, Guilak F. Human adipose-derived cells: an update on the transition to clinical translation. Regen Med 2012; 7:225-35. [PMID: 22397611 DOI: 10.2217/rme.11.119] [Citation(s) in RCA: 122] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
The pace of discovery involving adipose-derived cells continues to accelerate at both the preclinical and clinical translational levels. Adipose tissue is a source of freshly isolated, heterogeneous stromal vascular fraction cells and culture-expanded, adherent and relatively homogeneous adipose stromal/stem cells. Both populations display regenerative capacity in soft and hard tissue repair, ischemic insults and autoimmune diseases. While their major mechanism of action has been attributed to both direct lineage differentiation and/or paracrine factor release, current evidence favors a paracrine mechanism. Over 40 clinical trials using adipose-derived cells conducted in 15 countries have been registered with the NIH, the majority of which are Phase I or Phase I/II safety studies. This review focuses on the literature of the past 2 years in order to assess the status of clinical and preclinical studies on adipose-derived cell therapies for regenerative medicine.
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Affiliation(s)
- Jeffrey M Gimble
- Center for Stem Cell Research & Regenerative Medicine, Department of Pharmacology, Tulane University Health Science Center, New Orleans, LA 70112, USA.
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Rada T, Reis RL, Gomes ME. Adipose tissue-derived stem cells and their application in bone and cartilage tissue engineering. TISSUE ENGINEERING PART B-REVIEWS 2010; 15:113-25. [PMID: 19196117 DOI: 10.1089/ten.teb.2008.0423] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The adipose tissue was considered a reserve of energy until the '80s, when it was found that this tissue was involved in the metabolism of sex steroids such as estrogens. From then on, the importance attributed to this tissue radically changed as it was then considered an active organ, involved in important functions of the human body. In 2001, for the first time, the existence of stem cells within this tissue was reported, and since then, this tissue has been gaining an increased importance as a stem cell source for a wide range of potential applications in cell therapies and/or tissue engineering and regenerative medicine strategies, mainly due to its wide availability and easy access. This manuscript provides an overview on adipose stem cells (i.e., adipose tissue-derived stem cells, ASCs) considering the tissue of origin, the niche of the ASCs, and their phenotype in all aspects. In this paper it is also discussed the markers that have been used for the characterization of these cells, their differentiation properties, and their immunological reactivity, reporting studies from 2001 until this date. The ASCs are also compared with bone marrow stem cells (BMSCs), until now considered as the gold standard source of stem cells, underlining the common characteristics and the differences between the stem cells obtained from these two sources, as well as the advantages and disadvantages of their potential use in different applications. Finally, this review will also focus on the potential application of ASCs in tissue engineering applications, particularly in the regeneration of bone and cartilage, commenting on the progress of this approach and future trends of the field.
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Affiliation(s)
- Tommaso Rada
- 3B's Research Group-Biomaterials, Biodegradables and Biomimetics, Department of Polymer Engineering, University of Minho, Braga, Portugal
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Bai X, Alt E. Myocardial regeneration potential of adipose tissue-derived stem cells. Biochem Biophys Res Commun 2010; 401:321-6. [PMID: 20833143 DOI: 10.1016/j.bbrc.2010.09.012] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2010] [Accepted: 09/05/2010] [Indexed: 12/17/2022]
Abstract
Various tissue resident stem cells are receiving attention from basic scientists and clinicians as they hold promise for myocardial regeneration. For practical reasons, adipose tissue-derived stem cells (ASCs) are attractive cells for clinical application in repairing damaged myocardium based on the following advantages: abundant adipose tissue in most patients and easy accessibility with minimally invasive lipoaspiration procedure. Several recent studies have demonstrated that both cultured and freshly isolated ASCs could improve cardiac function in animal model of myocardial infarction. The mechanisms underlying the beneficial effect of ASCs on myocardial regeneration are not fully understood. Growing evidence indicates that transplantation of ASCs improve cardiac function via the differentiation into cardiomyocytes and vascular cells, and through paracrine pathways. Paracrine factors secreted by injected ASCs enhance angiogenesis, reduce cell apoptosis rates, and promote neuron sprouts in damaged myocardium. In addition, Injection of ASCs increases electrical stability of the injured heart. Furthermore, there are no reported cases of arrhythmia or tumorigenesis in any studies regarding myocardial regeneration with ASCs. This review summarizes the characteristics of both cultured and freshly isolated stem cells obtained from adipose tissue, their myocardial regeneration potential, and the underlying mechanisms for beneficial effect on cardiac function, and safety issues.
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Affiliation(s)
- Xiaowen Bai
- Department of Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030, USA
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Bai X, Yan Y, Song YH, Seidensticker M, Rabinovich B, Metzele R, Bankson JA, Vykoukal D, Alt E. Both cultured and freshly isolated adipose tissue-derived stem cells enhance cardiac function after acute myocardial infarction. Eur Heart J 2009; 31:489-501. [PMID: 20037143 DOI: 10.1093/eurheartj/ehp568] [Citation(s) in RCA: 166] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
AIMS We assessed whether freshly isolated human adipose tissue-derived cells (fhADCs) or cultured human adipose tissue-derived stem cells (hASCs) have beneficial effects on cardiac function after myocardial infarction (MI), whether the injected cells can survive long term, and whether their effects result from direct differentiation or paracrine mechanisms. METHODS AND RESULTS Myocardial infarction was experimentally induced in severe combined immunodeficient mice, and either fhADCs, cultured hASCs, or phosphate-buffered saline was injected into the peri-infarct region. Myocardial function improved significantly in mice treated with hASCs or fhADCs 4 weeks after MI. Immunofluorescence revealed that grafted hASCs and fhADCs underwent cardiomyogenic differentiation pathway, as indicated by expression of connexin 43 and troponin I in a fusion-independent manner. Some of the injected cells integrated with host cardiomyocytes through connexin 43, and others were incorporated into newly formed vessels. Human adipose tissue-derived stem cells survived in injured hearts up to 4 months, as detected by luciferase-based bioluminescence imaging. Vascular density was significantly increased, and fewer apoptotic cells were present in the peri-infarct region of cell-injected mice. CONCLUSION This is the first study to systematically compare the effects of fhADCs and hASCs on myocardial regeneration. Both cell types engraft into infarcted myocardium, survive, and improve myocardial function, suggesting that fhADCs, like hASCs, are a promising alternative cell source for myocardial repair after MI.
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Affiliation(s)
- Xiaowen Bai
- Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, SCRB2, Unit 951, 7435 Fannin Street, Houston, TX 77054, USA
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Cai L, Johnstone BH, Cook TG, Tan J, Fishbein MC, Chen PS, March KL. IFATS collection: Human adipose tissue-derived stem cells induce angiogenesis and nerve sprouting following myocardial infarction, in conjunction with potent preservation of cardiac function. Stem Cells 2009; 27:230-7. [PMID: 18772313 DOI: 10.1634/stemcells.2008-0273] [Citation(s) in RCA: 180] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The administration of therapeutic cell types, such as stem and progenitor cells, has gained much interest for the limitation or repair of tissue damage caused by a variety of insults. However, it is still uncertain whether the morphological and functional benefits are mediated predominantly via cell differentiation or paracrine mechanisms. Here, we assessed the extent and mechanisms of adipose-derived stromal/stem cells (ASC)-dependent tissue repair in the context of acute myocardial infarction. Human ASCs in saline or saline alone was injected into the peri-infarct region in athymic rats following left anterior descending (LAD) coronary artery ligation. Cardiac function and structure were evaluated by serial echocardiography and histology. ASC-treated rats consistently exhibited better cardiac function, by all measures, than control rats 1 month following LAD occlusion. Left ventricular (LV) ejection fraction and fractional shortening were improved in the ASC group, whereas LV remodeling and dilation were limited in the ASC group compared with the saline control group. Anterior wall thinning was also attenuated by ASC treatment, and post-mortem histological analysis demonstrated reduced fibrosis in ASC-treated hearts, as well as increased peri-infarct density of both arterioles and nerve sprouts. Human ASCs were persistent at 1 month in the peri-infarct region, but they were not observed to exhibit significant cardiomyocyte differentiation. Human ASCs preserve heart function and augment local angiogenesis and cardiac nerve sprouting following myocardial infarction predominantly by the provision of beneficial trophic factors.
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Affiliation(s)
- Liying Cai
- Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, USA
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Abstract
So far, the major safety issue raised by the use of stem cells for cardiac repair has been the occurrence of ventricular arrhythmias, particularly after skeletal myoblast transplantation. Although one cannot refute a potential intrinsic arrhythmogenicity of stem cells, primarily related to their common lack of electromechanical integration into the recipient myocardium, it is also important to recognize that patients eligible for cell replacement therapy are prone to develop arrhythmias because of their underlying ischemic heart disease. Another confounding factor is the method used for the intramyocardial delivery of the cells, which can cause enough inflammatory tissue damage to further increase ventricular irritability on top of an already high baseline level. Thus any strategy designed to minimize the risk of stem cell-associated ventricular arrhythmias should take into account, besides the cell-specific ability to appropriately couple with host cardiomyocytes, the method of cell transfer and the nature of the myocardial environment targeted for cell engraftment. A more accurate characterization of the baseline risk of arrhythmias in these patients would thus be helpful for better assessing the respective contribution of the donor cells and the host myocardium to these complications. The risk-to-benefit ratio of stem cell therapy will finally have to be revisited in light of the fact that because this baseline risk is usually high, most of these patients will in any way be fitted with an implantable defibrillator.
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Affiliation(s)
- Philippe Menasché
- Department of Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75015 Paris, France.
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Current world literature. Curr Opin Organ Transplant 2009; 14:103-11. [PMID: 19337155 DOI: 10.1097/mot.0b013e328323ad31] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Fernandes S, van Rijen HVM, Forest V, Evain S, Leblond AL, Mérot J, Charpentier F, de Bakker JMT, Lemarchand P. Cardiac cell therapy: overexpression of connexin43 in skeletal myoblasts and prevention of ventricular arrhythmias. J Cell Mol Med 2009; 13:3703-12. [PMID: 19438811 PMCID: PMC3189515 DOI: 10.1111/j.1582-4934.2009.00740.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Cell-based therapies have great potential for the treatment of cardiovascular diseases. Recently, using a transgenic mouse model Roell et al. reported that cardiac engraftment of connexin43 (Cx43)-overexpressing myoblasts in vivo prevents post-infarct arrhythmia, a common cause of death in patients following heart attack. We carried out a similar study but in a clinically relevant context via transplantation of autologous connexin43-overexpressing myoblasts in infarcted rats. Seven days after coronary ligation, rats were randomized into three groups: a control group injected with myoblasts, a null group injected with myoblasts transduced with an empty lentivirus vector (null) and a Cx43 group injected with myoblasts transduced with a lentivirus vector encoding connexin43. In contrast to Roell’s report, arrhythmia occurrence was not statistically different between groups (58%, 64% and 48% for the control (n= 12), null (n= 14) and Cx43 (n= 23) groups, respectively, P= 0.92). Using ex vivo intramural monophasic action potential recordings synchronous electrical activity was observed between connexin43-overexpressing myoblasts and host cardiomyocytes, whereas such synchrony did not occur in the null-transduced group. This suggests that ex vivo connexin43 gene transfer and expression in myoblasts improved intercellular electrical coupling between myoblasts and cardiomyocytes. However, in our model such electrical coupling was not sufficient to decrease arrhythmia induction. Therefore, we would suggest a note of caution on the use of combined Cx43 gene and cell therapy to prevent post-infarct arrhythmias in heart failure patients.
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Phillips MI, Tang YL, Pinkernell K. Stem cell therapy for heart failure: the science and current progress. Future Cardiol 2008; 4:285-98. [DOI: 10.2217/14796678.4.3.285] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Cell therapy, particularly with stem cells, has created great interest as a solution to the fact that there are limited treatments for postischemic heart disease and none that can regenerate damaged heart cells to strengthen cardiac performance. From the first efforts with myoblasts to recent clinical trials with bone marrow-derived stem cells, early reports of cell therapy suggest improvement in cardiac performance as well as other clinical end points. Based on these exciting but tentative results, other stem cell types are being explored for their particular advantages as a source of adult stem cells. Autologous adipose-derived stem cells are multilinear and can be obtained relatively easily in large quantities from patients; cardiac-derived stem cells are highly appropriate for engraftment in their natural niche, the heart. Human umbilical cord blood cells are potentially forever young and allogenic adult mesenchymal stem cells appear not to evoke the graft versus host reaction. Human embryonic stem cells are effective and can be scaled up for supply purposes. The recent discovery of induced pluripotentcy in human adult stem cells, with only three transcription factor genes, opens a whole new approach to making autologous human pluripotent stem cells from skin or other available tissues. Despite the excitement, stem cells may have to be genetically modified with heme oxygenase, Akt or other genes to survive transplantation in a hypoxic environment. Homing factors and hormones secreted from transplanted stem cells may be more important than cells if they provide the necessary stimulus to trigger cardiac regrowth to replace scar tissue. As we await results from larger and more prolonged clinical trials, the science of stem cell therapy in cardiac disease keeps progressing.
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Affiliation(s)
- M Ian Phillips
- Keck Graduate Institute, Stem Cell Labs, 535 Watson Drive, Claremont, CA 91711, USA
| | - Yao Liang Tang
- Keck Graduate Institute, Stem Cell Labs, 535 Watson Drive, Claremont, CA 91711, USA
| | - Kai Pinkernell
- Cytori Therapeutics Inc., 3020 Callan Road, San Diego, CA 92121, USA
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