Our primarily focus is the development of a functional tissue-engineered bio-active cardiac patch.
The use of a fully functional cardiac patch that can be surgically attached and integrated onto the MI region of the injured heart is seen as having the greatest potential to restore cardiac function effectively. Our approach is comprehensive; ensuring the use of a stable reparative cell source, adequate in vitro culture conditions to precondition the cells, an appropriate scaffold material with 3D architecture to promote vascularization and support cell organization and integration, and a precise surgical placement for subsequent integration with the host myocardium.
Various stem and progenitor cells are being utilized; several scaffold types, of synthetic and natural origin, are being developed in parallel with emphasis on controllable and reproducible processing methodologies such as decellularization, electrospinning, meltspinning, robotic printing etc. The cell-seeded scaffolds are further cultivated in vitro using custom-designed bioreactor systems for cardiac preconditioning, and the tissue patches are surgically implanted into the ischemic heart using MI models in small and large animals. Entrapment of cells within core-shell electrospun scaffold fibers.
European Cells and Materials , In-press Characterization of a bioactive fiber scaffold with entrapped HUVECs in coaxial electrospun core-shell fiber. Biomaterials , 4, Journal of Biomaterials Science, Polymer Edition. Steele, Charlotte L. Huang, Evelyne B. Chye, Marcelle Machluf, Freddy Y.
- Stem cells for cardiac regeneration by cell therapy and myocardial tissue engineering..
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- 2 CARDIAC ECM.
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Collagen-cellulose composite thin films that mimic soft-tissue and allow stem-cell orientation. Journal of Materials Science, Materials in Medicine , 24 8 , Ting, Udi Sarig, Evelyne B. Nguyen, Freddy Y. Boey, Subbu S. Venkatraman, Marcelle Machluf.
A mathematical model for analyzing the elasticity, viscosity and failure of soft tissue: comparison of native and decellularized porcine cardiac extracellular matrix for tissue engineering. Tissue Engineering, Part C, Methods , 19 8 , — A mathematical model predicting the co-culture dynamics of endothelial and mesenchymal stem cells for tissue regeneration.
Tissue Engineering, Part A , 19 9—10 , — Thick acellular heart extracellular matrix with inherent vasculature: a potential platform for myocardial tissue regeneration. Tissue Engineering , Part A, 18 19 — 20 , — Huang, Seranya Kumar, Scott A. Cardiac progenitor cells CPCs based therapy is considered a valid alternative to heart transplant, but several issues concerning the transplanted cells viability, retention and therapeutic effect need to be solved.
Tissue engineering, mixing synthetic or natural polymers with injected cells, could represent the way through which overcomes shortages and set up an effective cardiac regenerative therapy. Nowadays, it is well known that cardiac extracellular matrix ECM provides structural and functional integrity, affects cardiac function, development and physiologic repair. In this optic, ECM and ECM-like materials represent functional and biocompatible tools with a great potential to serve as natural or nature-mimicking scaffolds in the field of regenerative medicine.
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The aim of the present work is to provide an overview on the state of the art and recent advantages on CPCs and scaffold-based therapy for heart regeneration. Despite considerable achievements in term of early diagnosis and prevention, ischemic heart disease still represents the leading cause of death and disability worldwide and its frequency is increasing. In , it has been established that ischemic heart disease accounts for almost 1.
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Nowadays, heart transplantation represents the only successful therapeutic approach for end-stage heart failure HF patients. Unfortunately, organ availability and immunological issues heavily hinder this strategy. The need to establish effective therapies, to improve survival and quality of life of the patients, has led researchers to investigate and develop alternative therapies able to protect, regenerate and functionally restore the damaged myocardium.
The mammalian heart has been considered, for a long time, as a terminally differentiated organ incapable of regenerating after injury. In recent years, many evidences demonstrated that cardiomyocytes, during aging and after injury, are able to reentry in the cell cycle and promote cell renewal [2,3]. In addition, it has been identified the presence of several resident cardiac progenitor cells CPCs population that, after myocardial infarction MI , are able to proliferate and differentiate into the cardiac lineages .
Unfortunately, inflammatory processes following cardiac injury, in addition to the unsuitable ischemic microenvironment and the lack of oxygen, are able to affect this endogenous regenerative process exacerbating tissue damages and promoting adverse remodeling. Accordingly, cardiac cell therapy CCT approach, based on isolation, expansion and injection of CPCs, might be a valid alternative to promote and support heart regeneration [5,6]. However, despite the encouraging preclinical and clinical results, these treatments have shown very limited improvement in the long term [7—9]. The limited engraftment and the subsequent reduced proliferation and differentiation potential of the transplanted cells, due to the interaction between injected CPCs, extracellular matrix ECM components and the local tissue condition, represent another important issue for the therapeutic outcome [10,11].
Therefore, the synergy between CCT and tissue-engineering approaches, able to increase the engraftment and regenerative potential of injected cells, in addition to their anti-remodeling capacities and the possibility to stimulate resident cells, could represent a beneficial and valid alternative . In the present review, we discuss the therapeutic role of CPC population and provide an overview on the state of the art and recent advantages on scaffold-based therapy for infarcted myocardium in order to understand which step will be the next to be taken to improve cardiac regenerative medicine.
ECM is a key functional tissue structure, including growth factors, fibrous proteins and glycosaminoglycans GAGs produced and secreted by resident cells, able to create an in vivo specialized microenvironment in which cells survival and biological activity is preserved . In the heart, ECM provides structural and functional integrity, mediating the mechanical connection among cardiomyocytes, cardiac fibroblasts CFs and blood vessels, able to guide organ development and physiologic repair and to affect cardiac functions [14—16].
Regenerative Medicine & Stem Cells
CFs, that together with endothelial cells represent the higher portion of resident non-myocyte cells, are able to produce ECM and, at the same time, maintain its homeostasis, through the production of matrix metalloproteinases MMPs , a group of ECM-degrading enzymes able to break down all the protein components of the matrix, and the tissue inhibitors of metalloproteinases TIMPs [17,18].
Several pre-clinical and clinical studies have underlined that an imbalance in ECM remodelling, which means an alteration between the MMPs and TIMPs production and function, is detrimental in the failing heart [19—23].
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- CPCs and ECM: A Good Mix for Cardiac Regeneration-Hapres-An Academic Publisher.
In fact, this maladaptive remodelling, bringing to an altered arrangement and reduced cross-linking between collagen fibres, contributes to reduce systolic performance, decreased compliance and diastolic dysfunction in failing human heart . Furthermore, it has been demonstrated that during this cardiac adverse remodeling, variations in ECM composition and its mechanical features can interfere with the cardiogenic potential of resident or transplanted CPCs . In this optic, ECM and ECM-like materials represent functional and biocompatible tools with a great potential to serve as natural or nature-mimicking scaffolds in the field of regenerative medicine [30,31].
The heart has been considered for a long time as a terminally differentiated organ with no intrinsic capacity to regenerate after myocardial injury.
This concept is now being challenged and several evidences demonstrated that into the adult mammalian heart, both in normal and pathological conditions, myocytes are able to undergo mitosis and cytokinesis . Furthermore, different resident cardiac progenitor cells CPCs populations have been identified both in the embryonic and adult heart and their potential use for cardiac regeneration has been deeply investigated for years . During the embryonic development, multipotent cardiovascular progenitors MCPs , which derive from the mesodermal lineage, contribute to the heart formation in two ways .
On one side, the First Heart Field FHF , which is the classical cardiac crescent consisting of T-Box 5 TBX5 positive cells, is known to contribute to the formation of the left ventricle and, partially, of the atria. Due to their ability to differentiate into cardiac and smooth muscle and vascular endothelium, MCPs represent a promising regenerative tool for heart repair [37,38].
In fact, embryonic stem cells ESCs have been deeply studied not only to investigate cardiac development and the function of human and murine heart cells, but also to determine the basic strategies of regenerative cell therapy [39—41]. Furthermore, several in vitro protocols have been developed to stimulate human ESCs differentiation in cardiomyocytes, providing a morphology and an expression profile similar to that of adult cardiomyocytes .
adedemycifew.ga Briefly, cardiomyocytes markers are categorized in two principal groups: early and late differentiation. Even if their physiologic role in homeostasis and activation after injury still remains unclear, CPCs can be isolated from adult human and mammalian hearts with different approaches [45—47]. Interestingly, in it has been demonstrated for the first time that human CPCs can be isolated, starting from explant cultures of percutaneous endomyocardial biopsy specimens, through their capacity to form spontaneously 3D spherical clusters, called cardiospheres CSps [50—53].
CSps represent a perfect niche microenvironment in which it is possible to recognize, according to their expression pattern, two distinct compartments. The core, in which cells are characterized by a high proliferation rate, presents a cardiac progenitor immunophenotype dominated by the expression of stem cell and cardiomyocyte-related antigens, such as c-KIT, GATA-4, NKX2.
Although it has been analysed the therapeutic potential of other non-cardiac stem cell sources, such as embryonic cells, bone marrow-derived mesenchymal stem cells, endothelial progenitor cells, myoblasts and induced pluripotent stem cells, many evidences underlined that resident CPCs, especially CDCs, represent the better candidate for cardiac regenerative medicine [5, 56—59].
In , Li et al. Subsequently, other preclinical studies confirmed that CDCs therapy has multiple beneficial effects on the damaged myocardium, such as enhancement of cell survival, increase of blood supply and viable mass, reduction of inflammation and scar size and, in acute MI pig models, prevention of ischemic injury after reperfusion [60—65].
These encouraging preclinical results have paved the way to CDCs-based clinical trials. In the 6-month follow-up, the safety of the cells was demonstrated in association with a reduction of the infarct scar size and an increase in myocardial viability and contractility . Furthermore, after 1 year from the treatment, even if ventricular volumes and left ventricular ejection fraction LVEF did not increase, myocardial regeneration has been achieved, strengthened the therapeutic potential of CDCs .
Unfortunately, the study is still in progress and results are not yet available. Interestingly, even if CPCs show a high differentiation potential in vitro , recent studies suggest that the in vivo direct differentiation following transplantation is not the primary mechanism by which these cells promote cardiac recovery . In fact, a great proportion of CPCs therapeutic effects were shown to be attributable to indirect mechanisms of action able to exert protective and beneficial effects on the endogenous tissue.
In a comparative study, it has been analysed the CPCs secretome profile, consisting of humoral factors, proteins, and molecules, underlining a highly complex and biological activity able to provide significant paracrine benefits than other progenitor populations, such as the bone marrow or adipose tissue . Indeed, CPCs secretome exerts significant anti-apoptotic effects, promotes the recruitment of endogenous progenitors and the activation of endogenous cardioblasts [69—71].
In this context, also CPCs-derived exosomes are able to exert, once released in the extracellular microenvironment, positive therapeutic effects through multiple mechanisms interacting with different target cells, such as endothelial cells and cardiomyocytes [72—74]. Overall, despite all these encouraging results many critical issues, including the challenges of electrical coupling, undetermined mechanism aspects and, above all, the long term engraftment and survival of injected cells, should be addressed before CPCs could be considered as a strong therapeutic tool for regenerative medicine applications .