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Plasticity and cardiovascular applications of multipotent adult progenitor cells

Cardiovascular disease is the leading cause of death worldwide, which has encouraged the search for new therapies that enable the treatment of patients in palliative and curative ways. In the past decade, the potential benefit of transplantation of cells that are able to substitute for the injured tissue has been studied with several cell populations, such as stem cells. Some of these cell populations, such as myoblasts and bone marrow cells, are already being used in clinical trials. The laboratory of CM Verfaillie has studied primitive progenitors, termed multipotent adult progenitor cells, which can be isolated from adult bone marrow. These cells can differentiate in vitro at the single-cell level into functional cells that belong to the three germ layers and contribute to most, if not all, somatic cell types after blastocyst injection. This remarkably broad differentiation potential makes this particular cell population a candidate for transplantation in tissues in need of regeneration. Here, we focus on the regenerative capacity of multipotent adult progenitor cells in several ischemic mouse models, such as acute and chronic myocardial infarction and limb ischemia

Generation of NKX2.5(GFP) Reporter Human iPSCs and Differentiation Into Functional Cardiac Fibroblasts

Direct cardiac reprogramming has emerged as an interesting approach for the treatment and regeneration of damaged hearts through the direct conversion of fibroblasts into cardiomyocytes or cardiovascular progenitors. However, in studies with human cells, the lack of reporter fibroblasts has hindered the screening of factors and consequently, the development of robust direct cardiac reprogramming protocols.In this study, we have generated functional human NKX2.5(GFP) reporter cardiac fibroblasts. We first established a new NKX2.5(GFP) reporter human induced pluripotent stem cell (hiPSC) line using a CRISPR-Cas9-based knock-in approach in order to preserve function which could alter the biology of the cells. The reporter was found to faithfully track NKX2.5 expressing cells in differentiated NKX2.5(GFP) hiPSC and the potential of NKX2.5-GFP + cells to give rise to the expected cardiac lineages, including functional ventricular- and atrial-like cardiomyocytes, was demonstrated. Then NKX2.5(GFP) cardiac fibroblasts were obtained through directed differentiation, and these showed typical fibroblast-like morphology, a specific marker expression profile and, more importantly, functionality similar to patient-derived cardiac fibroblasts. The advantage of using this approach is that it offers an unlimited supply of cellular models for research in cardiac reprogramming, and since NKX2.5 is expressed not only in cardiomyocytes but also in cardiovascular precursors, the detection of both induced cell types would be possible. These reporter lines will be useful tools for human direct cardiac reprogramming research and progress in this field.This work was supported by PID 2019-107150RB-I00/AEI/ 10.13039/501100011033 to XC-V; by the “Ramón y Cajal” State Program, Ministry of Economy and Competitivenes

Generation of an induced pluripotent stem cell line (ESi107-A) from a transthyretin amyloid cardiomyopathy (ATTR-CM) patient carrying a p.Ser43Asn mutation in the TTR gene

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a life-threatening disease caused by the abnormal production of misfolded TTR protein by liver cells, which is then released systemically. Its amyloid deposition in the heart is linked to cardiac toxicity and progression toward heart failure. A human induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells (PBMCs) from a patient suffering familial transthyretin amyloid cardiomyopathy carrying a c.128G>A (p.Ser43Asn) mutation in the TTR gene. This iPSC line offers a useful resource to study the disease pathophysiology and a cell-based model for therapeutic discovery

Anisotropy of magnetic susceptibility of the Pyrenean granites

In this paper, we report on a compilation of more than 2200 sites (more than 10,000 individual measurements) where anisotropy of magnetic susceptibility (AMS) was studied in granites from the Variscan Pyrenees. The standardization and homogenization of this information has allowed us to produce three Main Maps that synthesize all the information related with the AMS of the Pyrenean granites. We also describe the problems found during the construction of the database (variable geo-positioning, different published information, etc.). The information derived from 21 granite bodies, the database, and the synthesis maps (magnetic susceptibility, Km, and the orientation of the magnetic foliation, plane perpendicular to k3, and of the magnetic lineation, k1) allow us to see for the first time a complete image of this important kinematic and petrographic indicator

MAPC transplantation confers a more durable benefit than AC133+ cell transplantation

There is a need for comparative studies to determine which cell types are better candidates to remedy ischemia. Here, we compared human AC133+ cells and Multipotent Adult Progenitor Cells (hMAPC) in a mouse model reminiscent of critical limb ischemia. hMAPC or hAC133+ cell transplantation induced a significant improvement in tissue perfusion (measured by microPET) 15 days post-transplantation compared to controls. This improvement persisted for 30 days in hMAPC-treated but not in hAC133+-injected animals. While transplantation of hAC133+ cells promoted capillary growth, hMAPC transplantation also induced collateral expansion, decreased muscle necrosis/fibrosis and improved muscle regeneration. Incorporation of differentiated hAC133+ or hMAPC progeny into new vessels was limited, however, a paracrine angio/arteriogenic effect was demonstrated in animals treated with hMAPC. Accordingly, hMAPC-, but not hAC133+-conditioned media, stimulated vascular cell proliferation and prevented myoblast, endothelial and smooth muscle cell apoptosis in vitro. Our study suggests that although hAC133+ cell and hMAPC transplantation bothcontribute to vascular regeneration in ischemic limbs, hMAPC exert a more robust effect through trophic mechanisms, which translated into collateral and muscle fiber regeneration. This, in turn, conferred tissue protection and regeneration with longer-term functional improvement