346 research outputs found
Cardiac progenitor cells. The matrix has you
No full textComponents of the cardiac extracellular matrix (ECM) are synthesized by residing cells and are continuously remodeled by them. Conversely, residing cells (including primitive cells) receive constant biochemical and mechanical signals from the ECM that modulate their biology. The pathological progression of heart failure affects all residing cells, inevitably causing profound changes in ECM composition and architecture that, in turn, impact on cell phenotypes. Any regenerative medicine approach must aim at sustaining microenvironment conditions that favor cardiogenic commitment of therapeutic cells and minimize pro-fibrotic signals, while conversely boosting the capacity of therapeutic cells to counteract adverse remodeling of the ECM. In this Perspective article, we discuss multiple issues about the features of an optimal scaffold for supporting cardiac tissue engineering strategies with cardiac progenitor cells, and, conversely, about the possible antifibrotic mechanisms induced by cell therapy
Development of a biological scaffold from adult human skin for cardiovascular repair and regeneration
No full textCardiovascular diseases (CVDs) are still the leading cause of death and disabilities globally. Among CVDs, ischemic heart disease (IHD) has remained the leading cause of death worldwide in the last 16 years. IHD is caused by a sudden blockage of blood flow through coronary arteries that prevents the supply of oxygen and nutrients to the region of myocardium fed by the affected vessels. This condition causes the necrosis of the myocardium that is followed by a reparative process that starts from the infarcted area, but then involves, at later stages, also the uninjured myocardium, causing progressive fibrosis that may lead eventually to heart failure. Unfortunately, there is no cure for IHD and therapy can at best control symptoms and prevent a second ischemic event. The induction of post-infarction cardiac regeneration by the means of three factors, cells, scaffold and signals, is currently the target of cardiac tissue engineering. However, the field is still at its infancy and all three factors are yet to be defined. Since the ECM is the naturally occurring scaffold loaded with uncountable biological and mechanical signals, we aimed at obtaining and characterizing a biological three-dimensional scaffold for cardiac repair and regeneration from the adult human skin.
Our results provided evidence that the scaffold of decellularized human skin (d-HuSk) was acellular and had a preserved architecture, retained components of the ECM that are also typical of cardiac matrix and are critical for cardiac functions and mechanical properties of the ECM, like collagen, fibronectin, laminin, tenascin, elastin and GAGs. Additionally, growth factors stored in d-HuSk matrix were similar to those found in cardiac matrix and, as similar were the signals, similar were the effects of d-HuSk and cardiac matrix on human cardiac progenitor cells (hCPCs). Indeed, as emerged from cytocompatibility study, the environment offered by d-HuSk did not differ from the cardiac native one in supporting engraftment and survival of hCPCs. Furthermore, d-HuSk attracted hCPCs from the cardiac native matrix and sustained their differentiation and differentiation towards cardiac myocytes.
Therefore, d-HuSk is a biological scaffold that is easily obtained and might be used as an autograft. It shares to a large extent the composition of the cardiac native matrix, exerts on hCPCs similar effects in vitro and is also capable of stimulating their mobilization and engraftment. Overall, d-HuSk fulfills the key requirements needed for a scaffold to warrant its use in tissue engineering and, then, holds great promise as substitute for cardiac environment. Additionally, consisting of ECM proteins and being a storage of growth factors, d-HuSk might alone provide two of the three pillars of tissue engineering, namely the scaffold and the signals, and might be exploited as stand-alone scaffold to boost cardiac regeneration by recruiting resident cardiac progenitor cells, or as a cellularized scaffold by preparing a cardiac engineered tissue in vitro with the cell population of choice
Direct cell reprogramming as a new emerging strategy in cardiac regeneration
No full textMyocardial infarction (MI) is the current leading cause of mortality in the industrialised world. It is due to the irreversible death of billions of
cardiomyocytes, secondary to a condition of ischemia. This leads to the formation of a stiff fibrotic tissue, mainly populated by cardiac
fibroblasts (CFs). Currently, the only available therapy addressing the irreversible loss of functional cardiomyocytes is heart transplantation.
Different tissue engineering approaches and cell therapies are under investigation, aimed at recovering myocardial contractility. Main issues in
these strategies are the poor grafting and survival ability of implanted cells as well as the limited endogenous regenerative potential of adult
heart.
A new strategy is now emerging based on direct reprogramming of CFs into induced cardiomyocytes (iCMs) using transcriptional factors and/
or microRNAs (miRNAs) (miR-combo) [2-4]. Proof of concepts results of in vitro and in vivo conversion of mouse CFs into iCMs have been
published and in vitro direct reprogramming of human CFs has also been reported [1-3]. However, such strategy is still an immature approach:
reprogramming efficiency is low and partially reprogrammed non-beating cardiomyocytes have been generally obtained. Recently, in vitro direct
reprogramming efficiency of mouse CFs cultured in 3D fibrin hydrogels using miR-combo has resulted significantly increased compared to 2D
culture systems [4].
Based on these preliminary results, in this work we studied the miR-combo mediated reprogramming efficiency of human dermal and cardiac
fibroblasts cultured on hydrogel matrices, including fibrin, fibrin/laminin, fibrin/fibronectin and fibrin/cardiac biomatrix [5], by analysing cell
morphology, cell viability, change in gene expression (PCR analysis) and presence of markers of trans-differentiation by immunohistochemistry.
The 3D biomimetic hydrogels were able to increase reprogramming efficiency respect to 2D culture environment, both at a genetic and protein
level, with an enhancement in the expression of cardiac genes and cardiac proteins such as cardiac troponin I and alpha sarcomeric actinin.
[1] J.A. Batty et al. Eur. J. Heart Failure 2016; 18: 145
[2] T.M. Jayawardena et al. Circ. Res. 2012; 110: 1465-1473.
[3] T.M. Jayawardena et al. Circ. Res. 2015; 116:418-24.
[4] Y. Li et al. Scientific Reports 2016; 6: 38815.
[5] C. Castaldo et al. Biomed Res Int. 2013; 2013: 352370.
ERC-CoG 2017 BIORECAR project is acknowledge
- …
