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Elias-Llumbet A, Sharmin R, Berg-Sorensen K, Schirhagl R, Mzyk A. The Interplay between Mechanoregulation and ROS in Heart Physiology, Disease, and Regeneration. Adv Healthc Mater 2024; 13:e2400952. [PMID: 38962858 DOI: 10.1002/adhm.202400952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 05/16/2024] [Indexed: 07/05/2024]
Abstract
Cardiovascular diseases are currently the most common cause of death in developed countries. Due to lifestyle and environmental factors, this problem is only expected to increase in the future. Reactive oxygen species (ROS) are a key player in the onset of cardiovascular diseases but also have important functions in healthy cardiac tissue. Here, the interplay between ROS generation and cardiac mechanical forces is shown, and the state of the art and a perspective on future directions are discussed. To this end, an overview of what is currently known regarding ROS and mechanosignaling at a subcellular level is first given. There the role of ROS in mechanosignaling as well as the interplay between both factors in specific organelles is emphasized. The consequences at a larger scale across the population of heart cells are then discussed. Subsequently, the roles of ROS in embryogenesis, pathogenesis, and aging are further discussed, exemplifying some aspects of mechanoregulation. Finally, different models that are currently in use are discussed to study the topics above.
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Affiliation(s)
- Arturo Elias-Llumbet
- Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, Groningen, 9713AW, The Netherlands
- Laboratory of Genomic of Germ Cells, Biomedical Sciences Institute, Faculty of Medicine, University of Chile, Independencia, Santiago, 1027, Chile
| | - Rokshana Sharmin
- Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, Groningen, 9713AW, The Netherlands
| | | | - Romana Schirhagl
- Department of Biomedical Engineering, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, Groningen, 9713AW, The Netherlands
| | - Aldona Mzyk
- DTU Health Tech, Ørsteds Plads Bldg 345C, Kongens Lyngby, 2800, Denmark
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Wei Q, Gan C, Sun M, Xie Y, Liu H, Xue T, Deng C, Mo C, Ye T. BRD4: an effective target for organ fibrosis. Biomark Res 2024; 12:92. [PMID: 39215370 PMCID: PMC11365212 DOI: 10.1186/s40364-024-00641-6] [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: 07/05/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024] Open
Abstract
Fibrosis is an excessive wound-healing response induced by repeated or chronic external stimuli to tissues, significantly impacting quality of life and primarily contributing to organ failure. Organ fibrosis is reported to cause 45% of all-cause mortality worldwide. Despite extensive efforts to develop new antifibrotic drugs, drug discovery has not kept pace with the clinical demand. Currently, only pirfenidone and nintedanib are approved by the FDA to treat pulmonary fibrotic illness, whereas there are currently no available antifibrotic drugs for hepatic, cardiac or renal fibrosis. The development of fibrosis is closely related to epigenetic alterations. The field of epigenetics primarily studies biological processes, including chromatin modifications, epigenetic readers, DNA transcription and RNA translation. The bromodomain and extra-terminal structural domain (BET) family, a class of epigenetic readers, specifically recognizes acetylated histone lysine residues and promotes the formation of transcriptional complexes. Bromodomain-containing protein 4 (BRD4) is one of the most well-researched proteins in the BET family. BRD4 is implicated in the expression of genes related to inflammation and pro-fibrosis during fibrosis. Inhibition of BRD4 has shown promising anti-fibrotic effects in preclinical studies; however, no BRD4 inhibitor has been approved for clinical use. This review introduces the structure and function of BET proteins, the research progress on BRD4 in organ fibrosis, and the inhibitors of BRD4 utilized in fibrosis. We emphasize the feasibility of targeting BRD4 as an anti-fibrotic strategy and discuss the therapeutic potential and challenges associated with BRD4 inhibitors in treating fibrotic diseases.
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Affiliation(s)
- Qun Wei
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Cailing Gan
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Meng Sun
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yuting Xie
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Hongyao Liu
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Taixiong Xue
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Conghui Deng
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Chunheng Mo
- Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, State Key Laboratory of Biotherapy, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
| | - Tinghong Ye
- Laboratory of Gastrointestinal Cancer and Liver Disease, Department of Gastroenterology and Hepatology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Ningxia Medical University, Yin Chuan, 640100, China.
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3
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Chai C, Li S, Chen L, Song X. Causal association of calcific aortic valve stenosis and atrial fibrillation: a Mendelian randomization study. Sci Rep 2023; 13:20284. [PMID: 37985719 PMCID: PMC10662195 DOI: 10.1038/s41598-023-47770-w] [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: 04/03/2023] [Accepted: 11/18/2023] [Indexed: 11/22/2023] Open
Abstract
Calcific aortic valve stenosis (CAVS) is associated with an increased risk of atrial fibrillation (AF) in observational studies, but whether these associations are causal has not been determined. This study aimed to explore the potential causal relationship between CAVS and AF via Mendelian randomization (MR). Genetic variants from the genome-wide association study (GWAS) summary data of the European population for CAVS were used to investigate the association with AF. The inverse variance weighted (IVW) approach was used to obtain the primary causal inference, and several sensitivity analysis approaches, such as the MR‒Egger and weighted median (WM), were performed to assess the robustness of the results. A total of nineteen valid and independent genetic SNPs associated with CAVS were obtained from the GWAS database. Genetically predicted CAVS (OR: 1.105; 95% CI: 1.072-1.139; p = 8.60E-11) was associated with an increased risk of AF. Similar results were discovered in the sensitivity analyses by using MR Egger and weighted median approaches. An MR design was used to reduce confounding variables and the potential for reverse causality bias. The results provide genetic evidence that CAVS considerably increased the risk of AF.
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Affiliation(s)
- Chen Chai
- Emergency Center, Hubei Clinical Research Center for Emergency and Resuscitation, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuchang District, Wuhan, 430071, China
| | - Shoupeng Li
- Emergency Department, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan, China
| | - Lin Chen
- Emergency Department, Xiantao First People's Hospital Affiliated to Changjiang University, Xiantao, China
| | - Xiaobing Song
- Emergency Center, Hubei Clinical Research Center for Emergency and Resuscitation, Zhongnan Hospital of Wuhan University, No. 169, Donghu Road, Wuchang District, Wuhan, 430071, China.
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4
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Sagris M, Vardas EP, Theofilis P, Antonopoulos AS, Oikonomou E, Tousoulis D. Atrial Fibrillation: Pathogenesis, Predisposing Factors, and Genetics. Int J Mol Sci 2021; 23:6. [PMID: 35008432 PMCID: PMC8744894 DOI: 10.3390/ijms23010006] [Citation(s) in RCA: 166] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/07/2021] [Accepted: 12/15/2021] [Indexed: 02/07/2023] Open
Abstract
Atrial fibrillation (AF) is the most frequent arrhythmia managed in clinical practice, and it is linked to an increased risk of death, stroke, and peripheral embolism. The Global Burden of Disease shows that the estimated prevalence of AF is up to 33.5 million patients. So far, successful therapeutic techniques have been implemented, with a high health-care cost burden. As a result, identifying modifiable risk factors for AF and suitable preventive measures may play a significant role in enhancing community health and lowering health-care system expenditures. Several mechanisms, including electrical and structural remodeling of atrial tissue, have been proposed to contribute to the development of AF. This review article discusses the predisposing factors in AF including the different pathogenic mechanisms, sedentary lifestyle, and dietary habits, as well as the potential genetic burden.
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Affiliation(s)
- Marios Sagris
- 1st Cardiology Clinic, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.P.V.); (P.T.); (A.S.A.); (E.O.); (D.T.)
| | - Emmanouil P. Vardas
- 1st Cardiology Clinic, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.P.V.); (P.T.); (A.S.A.); (E.O.); (D.T.)
- Department of Cardiology, General Hospital of Athens “G. Gennimatas”, 11527 Athens, Greece
| | - Panagiotis Theofilis
- 1st Cardiology Clinic, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.P.V.); (P.T.); (A.S.A.); (E.O.); (D.T.)
| | - Alexios S. Antonopoulos
- 1st Cardiology Clinic, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.P.V.); (P.T.); (A.S.A.); (E.O.); (D.T.)
| | - Evangelos Oikonomou
- 1st Cardiology Clinic, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.P.V.); (P.T.); (A.S.A.); (E.O.); (D.T.)
- 3rd Department of Cardiology, “Sotiria” Thoracic Diseases Hospital of Athens, University of Athens Medical School, 11527 Athens, Greece
| | - Dimitris Tousoulis
- 1st Cardiology Clinic, ‘Hippokration’ General Hospital, School of Medicine, National and Kapodistrian University of Athens, 11528 Athens, Greece; (E.P.V.); (P.T.); (A.S.A.); (E.O.); (D.T.)
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Fujimoto KL, Yamawaki-Ogata A, Uto K, Usui A, Narita Y, Ebara M. Long term efficacy and fate of a right ventricular outflow tract replacement using an elastomeric cardiac patch consisting of caprolactone and D,L-lactide copolymers. Acta Biomater 2021; 123:222-229. [PMID: 33476828 DOI: 10.1016/j.actbio.2021.01.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Revised: 01/14/2021] [Accepted: 01/14/2021] [Indexed: 12/18/2022]
Abstract
For decades, researchers have investigated the ideal material for clinical use in the cardiovascular field. Several substitute materials are used clinically, but each has drawbacks. Recently we developed biodegradable and elastic poly(ε-caprolactone-co-D,L-lactide) (P(CL-DLLA)) copolymers by adjusting the CL/DLLA composition, and evaluated the long-term efficacy and outcomes of these copolymers when used for right ventricular outflow tract (RVOT) replacement. This P(CL-DLLA) material was processed into a circular patch and used to replace a surgical defect in the RVOT of adult rats. Control rats were implanted with expanded polytetrafluoroethylene (ePTFE). Histologic evaluation was performed at 8, 24, and 48 weeks post-surgery. All animals survived the surgery with no aneurysm formation or thrombus. In all periods, ePTFE demonstrated fibrous tissue. In contrast, at 8 weeks P(CL-DLLA) showed infiltration of macrophages and fibroblast-like cells into the remaining material. At 24 weeks, P(CL-DLLA) was absorbed completely, and muscle-like tissue was present with positive staining for α-sarcomeric actinin and cardiac troponin T (cTnT). At 48 weeks, the cTnT-positive area had increased. The biodegradable and elastic P(CL-DLLA) induced cardiac regeneration throughout the 48-week study period. Future application of this material as a cardiovascular scaffold seems promising. STATEMENT OF SIGNIFICANCE: Biomaterials for reconstruction of tissue deficiencies in cardiovascular surgery require having suitable mechanical properties for cardiac tissue and biodegradation resulting in native tissue growth. Several biodegradable polymers such as poly-ε-caprolactone (PCL) and polylactic acid (PLA) have excellent biocompatibility and already been widely used clinically. In general, PCL and PLA are quite mechanically rigid. Meanwhile, significant elasticity is required in the high-pressure environment of the heart while the material is being replaced by new tissue. The present study provides a novel four-armed crosslinked poly(ε-caprolactone-co-D,L-lactide) (i.e., P(CL-DLLA)) material for cardiac patch, which was demonstrated properties including tissue-compatible, super-elastic nature, that made it suitable for long-term, in vivo RVOT repair. This super-elastic biomaterial could be useful for reconstruction of various muscular tissues deficiencies.
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Hendrickson T, Mancino C, Whitney L, Tsao C, Rahimi M, Taraballi F. Mimicking cardiac tissue complexity through physical cues: A review on cardiac tissue engineering approaches. NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE 2021; 33:102367. [PMID: 33549819 DOI: 10.1016/j.nano.2021.102367] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 01/06/2021] [Accepted: 01/15/2021] [Indexed: 02/08/2023]
Abstract
Cardiovascular diseases are the number one killer in the world.1,2 Currently, there are no clinical treatments to regenerate damaged cardiac tissue, leaving patients to develop further life-threatening cardiac complications. Cardiac tissue has multiple functional demands including vascularization, contraction, and conduction that require many synergic components to properly work. Most of these functions are a direct result of the cardiac tissue structure and composition, and, for this reason, tissue engineering strongly proposed to develop substitute engineered heart tissues (EHTs). EHTs usually have combined pluripotent stem cells and supporting scaffolds with the final aim to repair or replace the damaged native tissue. However, as simple as this idea is, indeed, it resulted, after many attempts in the field, to be very challenging. Without design complexity, EHTs remain unable to mature fully and integrate into surrounding heart tissue resulting in minimal in vivo effects.3 Lately, there has been a growing body of evidence that a complex, multifunctional approach through implementing scaffold designs, cellularization, and molecular release appears to be essential in the development of a functional cardiac EHTs.4-6 This review covers the advancements in EHTs developments focusing on how to integrate contraction, conduction, and vascularization mimics and how combinations have resulted in improved designs thus warranting further investigation to develop a clinically applicable treatment.
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Affiliation(s)
- Troy Hendrickson
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston Methodist, Houston, TX, USA; Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, TX, USA; Texas A&M MD/PhD Program, Texas A&M Health Science Center, College Station, TX, USA
| | - Chiara Mancino
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston Methodist, Houston, TX, USA; Department of Electronics, Information and Bioengineering, Politecnico di Milano, Milano, (MI), Italy
| | - Lauren Whitney
- Texas A&M Biomedical Engineering, Texas A&M University, College Station, TX, USA
| | - Chris Tsao
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston Methodist, Houston, TX, USA
| | - Maham Rahimi
- Department of Cardiovascular Surgery, Houston Methodist, Houston, TX, USA
| | - Francesca Taraballi
- Center for Musculoskeletal Regeneration, Houston Methodist Research Institute, Houston Methodist, Houston, TX, USA; Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, TX, USA.
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Shin YJ, Shafranek RT, Tsui JH, Walcott J, Nelson A, Kim DH. 3D bioprinting of mechanically tuned bioinks derived from cardiac decellularized extracellular matrix. Acta Biomater 2021; 119:75-88. [PMID: 33166713 DOI: 10.1016/j.actbio.2020.11.006] [Citation(s) in RCA: 101] [Impact Index Per Article: 25.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 10/30/2020] [Accepted: 11/03/2020] [Indexed: 12/11/2022]
Abstract
3D bioprinting is a powerful technique for engineering tissues used to study cell behavior and tissue properties in vitro. With the right formulation and printing parameters, bioinks can provide native biological and mechanical cues while allowing for versatile 3D structures that recapitulate tissue-level organization. Bio-based materials that support cellular adhesion, differentiation, and proliferation - including gelatin, collagen, hyaluronic acid, and alginate - have been successfully used as bioinks. In particular, decellularized extracellular matrix (dECM) has become a promising material with the unique ability to maintain both biochemical and topographical micro-environments of native tissues. However, dECM has shown technical limitations for 3D printing (3DP) applications posed by its intrinsically low mechanical stability. Herein, we report hydrogel bioinks composed of partially digested, porcine cardiac decellularized extracellular matrix (cdECM), Laponite-XLG nanoclay, and poly(ethylene glycol)-diacrylate (PEG-DA). The Laponite facilitated extrusion-based 3DP, while PEG-DA enabled photo-polymerization after printing. Improving upon previously reported bioinks derived from dECM, our bioinks combine extrudability, shape fidelity, rapid cross-linking, and cytocompatibility in a single formulation (> 97% viability of encapsulated human cardiac fibroblasts and > 94% viability of human induced pluripotent stem cell derived cardiomyocytes after 7 days). The compressive modulus of the cured hydrogel bioinks was tunable from 13.4-89 kPa by changing the concentration of PEG-DA in the bioink formulation. Importantly, this span of mechanical stiffness encompasses ranges of tissue stiffness from healthy (compressive modulus ~5-15 kPa) to fibrotic (compressive modulus ~30-100 kPa) cardiac tissue states. The printed constructs demonstrated shape fidelity, adaptability to different printing conditions, and high cell viability following extrusion and photo-polymerization, highlighting the potential for applications in modeling both healthy and fibrotic cardiac tissue.
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High-Density Lipoprotein-Targeted Therapies for Heart Failure. Biomedicines 2020; 8:biomedicines8120620. [PMID: 33339429 PMCID: PMC7767106 DOI: 10.3390/biomedicines8120620] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 12/10/2020] [Accepted: 12/15/2020] [Indexed: 02/08/2023] Open
Abstract
The main and common constituents of high-density lipoproteins (HDLs) are apolipoprotein A-I, cholesterol, and phospholipids. Biochemical heterogeneity of HDL particles is based on the variable presence of one or more representatives of at least 180 proteins, 200 lipid species, and 20 micro RNAs. HDLs are circulating multimolecular platforms that perform divergent functions whereby the potential of HDL-targeted interventions for treatment of heart failure can be postulated based on its pleiotropic effects. Several murine studies have shown that HDLs exert effects on the myocardium, which are completely independent of any impact on coronary arteries. Overall, HDL-targeted therapies exert a direct positive lusitropic effect on the myocardium, inhibit the development of cardiac hypertrophy, suppress interstitial and perivascular myocardial fibrosis, increase capillary density in the myocardium, and prevent the occurrence of heart failure. In four distinct murine models, HDL-targeted interventions were shown to be a successful treatment for both pre-existing heart failure with reduced ejection fraction (HFrEF) and pre-existing heart failure with preserved ejection fraction (HFrEF). Until now, the effect of HDL-targeted interventions has not been evaluated in randomized clinical trials in heart failure patients. As HFpEF represents an important unmet therapeutic need, this is likely the preferred therapeutic domain for clinical translation.
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Thomas MC, Iyngkaran P. Forensic interrogation of diabetic endothelitis in cardiovascular diseases and clinical translation in heart failure. World J Cardiol 2020; 12:409-418. [PMID: 32879703 PMCID: PMC7439453 DOI: 10.4330/wjc.v12.i8.409] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 06/05/2020] [Accepted: 07/18/2020] [Indexed: 02/06/2023] Open
Abstract
Diabetic heart disease (DHD) can be classified as a primary consequence from several pathophysiological manifestation of diabetes mellitus (DM) on cardiac tissues or secondarily in extracardiac tissues and is encountered as either primary or secondary complications of DM. Endothelitis is inflammation of the vascular endothelium and is likely to be seen in the majority of patients who start to manifest an end organ complication of DM in this case DHD. Diabetes is a leading cause for many cardiovascular syndromes and diseases including congestive heart failure (CHF) however much remains unknown about the transition from diagnosed DM to clinical state and the contribution of the various mechanical and counterregulatory systems in the manifested complaint. Diastolic heart failure or heart failure with preserved ejection fraction (DHF/HFpEF), accounts for half of all CHF presentations, has DM as a major contributor, however, there remain large gaps in clinical and pathophysiological understanding. This review aims to explore the microscopic aspects in diabetic endothelitis and provide a clinical link to with context to HFpEF.
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Affiliation(s)
- Merlin C Thomas
- Department of Diabetes, Monash University, Melbourne 3004, Victoria, Australia.
| | - Pupalan Iyngkaran
- Werribee Mercy Sub School, School of Medicine Sydney, University of Notre Dame, Northcote 3070, Victoria, Australia
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Mazzola M, Di Pasquale E. Toward Cardiac Regeneration: Combination of Pluripotent Stem Cell-Based Therapies and Bioengineering Strategies. Front Bioeng Biotechnol 2020; 8:455. [PMID: 32528940 PMCID: PMC7266938 DOI: 10.3389/fbioe.2020.00455] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 04/21/2020] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases represent the major cause of morbidity and mortality worldwide. Multiple studies have been conducted so far in order to develop treatments able to prevent the progression of these pathologies. Despite progress made in the last decade, current therapies are still hampered by poor translation into actual clinical applications. The major drawback of such strategies is represented by the limited regenerative capacity of the cardiac tissue. Indeed, after an ischaemic insult, the formation of fibrotic scar takes place, interfering with mechanical and electrical functions of the heart. Hence, the ability of the heart to recover after ischaemic injury depends on several molecular and cellular pathways, and the imbalance between them results into adverse remodeling, culminating in heart failure. In this complex scenario, a new chapter of regenerative medicine has been opened over the past 20 years with the discovery of induced pluripotent stem cells (iPSCs). These cells share the same characteristic of embryonic stem cells (ESCs), but are generated from patient-specific somatic cells, overcoming the ethical limitations related to ESC use and providing an autologous source of human cells. Similarly to ESCs, iPSCs are able to efficiently differentiate into cardiomyocytes (CMs), and thus hold a real regenerative potential for future clinical applications. However, cell-based therapies are subjected to poor grafting and may cause adverse effects in the failing heart. Thus, over the last years, bioengineering technologies focused their attention on the improvement of both survival and functionality of iPSC-derived CMs. The combination of these two fields of study has burst the development of cell-based three-dimensional (3D) structures and organoids which mimic, more realistically, the in vivo cell behavior. Toward the same path, the possibility to directly induce conversion of fibroblasts into CMs has recently emerged as a promising area for in situ cardiac regeneration. In this review we provide an up-to-date overview of the latest advancements in the application of pluripotent stem cells and tissue-engineering for therapeutically relevant cardiac regenerative approaches, aiming to highlight outcomes, limitations and future perspectives for their clinical translation.
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Affiliation(s)
- Marta Mazzola
- Stem Cell Unit, Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy
| | - Elisa Di Pasquale
- Stem Cell Unit, Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy.,Institute of Genetic and Biomedical Research (IRGB) - UOS of Milan, National Research Council (CNR), Milan, Italy
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11
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Wang Z, Zhang L, Labib M, Chen H, Wei M, Poudineh M, Green BJ, Duong B, Das J, Ahmed S, Sargent EH, Kelley SO. Peptide-Functionalized Nanostructured Microarchitectures Enable Rapid Mechanotransductive Differentiation. ACS APPLIED MATERIALS & INTERFACES 2019; 11:41030-41037. [PMID: 31600052 DOI: 10.1021/acsami.9b13694] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/10/2023]
Abstract
Microenvironmental factors play critical roles in regulating stem cell fate, providing a rationale to engineer biomimetic microenvironments that facilitate rapid and effective stem cell differentiation. Three-dimensional (3D) hierarchical microarchitectures have been developed to enable rapid neural differentiation of multipotent human mesenchymal stromal cells (HMSCs) via mechanotransduction. However, low cell viability during long-term culture and poor cell recovery efficiency from the architectures were also observed. Such problems hinder further applications of the architectures in stem cell differentiation. Here, we present improved 3D nanostructured microarchitectures functionalized with cell-adhesion-promoting arginylglycylaspartic acid (RGD) peptides. These RGD-functionalized architectures significantly upregulated long-term cell viability and facilitated effective recovery of differentiated cells from the architectures while maintaining high differentiation efficiency. Efficient recovery of highly viable differentiated cells enabled the downstream analysis of morphology and protein expression to be performed. Remarkably, even after the removal of the mechanical stimulus provided by the 3D microarchitectures, the recovered HMSCs showed a neuron-like elongated morphology for 10 days and consistently expressed microtubule-associated protein 2, a mature neural marker. RGD-functionalized nanostructured microarchitectures hold great potential to guide effective differentiation of highly viable stem cells.
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Affiliation(s)
- Zongjie Wang
- The Edward S. Rogers Sr., Department of Electrical & Computer Engineering , University of Toronto , Toronto M5S 3G4 , Canada
- Institute for Biomaterials and Biomedical Engineering , University of Toronto , Toronto M5S 3G9 , Canada
| | - Libing Zhang
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto M5S 3M2 , Canada
| | - Mahmoud Labib
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto M5S 3M2 , Canada
| | - Haijie Chen
- The Edward S. Rogers Sr., Department of Electrical & Computer Engineering , University of Toronto , Toronto M5S 3G4 , Canada
| | - Mingyang Wei
- The Edward S. Rogers Sr., Department of Electrical & Computer Engineering , University of Toronto , Toronto M5S 3G4 , Canada
| | - Mahla Poudineh
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto M5S 3M2 , Canada
| | - Brenda J Green
- Institute for Biomaterials and Biomedical Engineering , University of Toronto , Toronto M5S 3G9 , Canada
| | - Bill Duong
- Department of Biochemistry, Faculty of Medicine , University of Toronto , Toronto M5S 1A8 , Canada
| | - Jagotamoy Das
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto M5S 3M2 , Canada
| | - Sharif Ahmed
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto M5S 3M2 , Canada
| | - Edward H Sargent
- The Edward S. Rogers Sr., Department of Electrical & Computer Engineering , University of Toronto , Toronto M5S 3G4 , Canada
| | - Shana O Kelley
- Institute for Biomaterials and Biomedical Engineering , University of Toronto , Toronto M5S 3G9 , Canada
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto M5S 3M2 , Canada
- Department of Biochemistry, Faculty of Medicine , University of Toronto , Toronto M5S 1A8 , Canada
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Poudineh M, Wang Z, Labib M, Ahmadi M, Zhang L, Das J, Ahmed S, Angers S, Kelley SO. Three-Dimensional Nanostructured Architectures Enable Efficient Neural Differentiation of Mesenchymal Stem Cells via Mechanotransduction. NANO LETTERS 2018; 18:7188-7193. [PMID: 30335391 DOI: 10.1021/acs.nanolett.8b03313] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/19/2023]
Abstract
Cell morphology and geometry affect cellular processes such as stem cell differentiation, suggesting that these parameters serve as fundamental regulators of biological processes within the cell. Hierarchical architectures featuring micro- and nanotopographical features therefore offer programmable systems for stem cell differentiation. However, a limited number of studies have explored the effects of hierarchical architectures due to the complexity of fabricating systems with rationally tunable micro- and nanostructuring. Here, we report three-dimensional (3D) nanostructured microarchitectures that efficiently regulate the fate of human mesenchymal stem cells (hMSCs). These nanostructured architectures strongly promote cell alignment and efficient neurogenic differentiation where over 85% of hMSCs express microtubule-associated protein 2 (MAP2), a mature neural marker, after 7 days of culture on the nanostructured surface. Remarkably, we found that the surface morphology of nanostructured surface is a key factor that promotes neurogenesis and that highly spiky structures promote more efficient neuronal differentiation. Immunostaining and gene expression profiling revealed significant upregulation of neuronal markers compared to unpatterned surfaces. These findings suggest that the 3D nanostructured microarchitectures can play a critical role in defining stem cell behavior.
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Affiliation(s)
- Mahla Poudineh
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Zongjie Wang
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Mahmoud Labib
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Moloud Ahmadi
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Libing Zhang
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Jagotamoy Das
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Sharif Ahmed
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Stephane Angers
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
| | - Shana O Kelley
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy , University of Toronto , Toronto , M5S 3M2 , Canada
- Institute for Biomaterials and Biomedical Engineering , University of Toronto , Toronto , M5S 3M2 , Canada
- Department of Biochemistry, Faculty of Medicine , University of Toronto , Toronto , M5S 1A8 , Canada
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