Luttun, A. (Aernout)
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- MAPC transplantation confers a more durable benefit than AC133+ cell transplantation(Cognizant Communication Corporation, 2010-08-17) Collantes, M. (María); Peñuelas-Sanchez, I. (Ivan); Uriz, M. (Maialen); Araña, M. (Miriam); Coppiello, G. (Giulia); Andreu, E.J. (Enrique José); Perez-Ilzarbe, M. (Maitane); Luttun, A. (Aernout); Ecay, M. (Margarita); Prieto, J. (Jesús); Beerens, M. (Manu); Prosper-Cardoso, F. (Felipe); Pelacho, B. (Beatriz); Abizanda-Sarasa, G. (Gloria); Aranguren, X.L. (Xabier L.)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.
- Plasticity and cardiovascular applications of multipotent adult progenitor cells(Nature Publishing Group, 2007) Gavira, J.J. (Juan José); Gutierrez-Perez, M. (María); Luttun, A. (Aernout); Mazo, M. (Manuel); Clavel, C. (C.); Prosper-Cardoso, F. (Felipe); Pelacho, B. (Beatriz); Abizanda-Sarasa, G. (Gloria); Aranguren, X.L. (Xabier L.); Verfaillie, C.M. (Catherine M.)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.
- Multipotent adult progenitor cell transplantation increases vascularity and improves left ventricular function after myocardial infarction(Wiley-Blackwell, 2007) Nakamura, Y. (Yasuhiro); Ross, J. (Jeff); Heremans, Y. (Y.); Zhang, J. (Jianyi); Lemke, B. (Brad); Luttun, A. (Aernout); Jiang, Y. (Y.); Nelson-Holte, M. (Molly); Hagenbrock, J. (J.); Prosper-Cardoso, F. (Felipe); Pelacho, B. (Beatriz); Verfaillie, C.M. (Catherine M.)Progressive contractile dysfunction of viable myocardium that surrounds a large infarct leads to heart failure following acute myocardial infarction (AMI). Experimental evidence indicates that cellular transplantation may improve the left ventricular (LV) contractile performance, even though the underlying mechanisms remain undefined. Here, we compared the effect of transplantation of murine multipotent adult progenitor cells (MAPCs), a population of adult bone marrow-derived cells that differentiate into cells of mesodermal, endodermal and ectodermal origin, with murine bone marrow cells (BMCs) or fibroblasts on post-infarct cardiac function by peri-infarct injection after coronary artery ligation in mice. We demonstrate that, in contrast to the other cell populations, transplantation of MAPCs significantly improved LV contractile function for at least 8 weeks posttransplantation and, although BMCs reduced infarct size, the decrease in scar size was substantially greater in MAPC-treated hearts. As neither MAPCs nor BMCs were present beyond 1 week, the beneficial effect was not due to differentiation and direct contribution of MAPCs to the vascular or cardiomyocyte compartment. Significantly more inflammatory cells were present in MAPC- than BMC-treated hearts at 1 week, which was accompanied by increased vascularity 8 weeks posttransplantation. We hypothesize that MAPCs indirectly contributed to these effects, by secreting inflammatory [monocyte chemoattractant protein-1 (MCP)-1], and vascular growth factors [vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF)-BB, and transforming growth factor (TGF)β1), and others, resulting in increased angiogenensis and cardioprotection.
- Quantification of miRNA-mRNA interactions(Public Library of Science, 2012) Vazquez, M. (Miguel); Pascual-Montano, A. (Alberto); Muniategui, A. (Ander); Luttun, A. (Aernout); Nogales-Cadenas, R. (Rubén); Prosper-Cardoso, F. (Felipe); Aguirre-Ena, X. (Xabier); Rubio, A. (Ángel); Aranguren, X.L. (Xabier L.)miRNAs are small RNA molecules (' 22nt) that interact with their corresponding target mRNAs inhibiting the translation of the mRNA into proteins and cleaving the target mRNA. This second effect diminishes the overall expression of the target mRNA. Several miRNA-mRNA relationship databases have been deployed, most of them based on sequence complementarities. However, the number of false positives in these databases is large and they do not overlap completely. Recently, it has been proposed to combine expression measurement from both miRNA and mRNA and sequence based predictions to achieve more accurate relationships. In our work, we use LASSO regression with non-positive constraints to integrate both sources of information. LASSO enforces the sparseness of the solution and the non-positive constraints restrict the search of miRNA targets to those with down-regulation effects on the mRNA expression. We named this method TaLasso (miRNA-Target LASSO).We used TaLasso on two public datasets that have paired expression levels of human miRNAs and mRNAs. The top ranked interactions recovered by TaLasso are especially enriched (more than using any other algorithm) in experimentally validated targets. The functions of the genes with mRNA transcripts in the top-ranked interactions are meaningful. This is not the case using other algorithms.TaLasso is available as Matlab or R code. There is also a web-based tool for human miRNAs at http://talasso.cnb.csic.es/.
- Multipotent adult progenitor cells sustain function of ischemic limbs in mice(American Society for Clinical Investigation, 2008) Zhu, X.H. (Xiao Hong); Chen, W. (W.); Ross, J.J. (John J.); Hendrickx, B. (B.); Peñuelas-Sanchez, I. (Ivan); Uriz, M. (Maialen); Du, F. (F.); Frommer, S.A. (S. A.); Zhang, X. (Xiaoliang); Schroeder, B.A. (Betsy A.); Zhang, Y. (Yi); McCue, J.D. (Jonathan D.); Luttun, A. (Aernout); Jiang, Y. (Y.); Seaborn, M.S. (Meredith S.); Nelson-Holte, M. (Molly); Harris, N.H. (N. H.); Hagenbrock, J. (J.); Prosper-Cardoso, F. (Felipe); Pelacho, B. (Beatriz); Chen, E. (E.); Billiau, A.D. (A.D.); Abizanda-Sarasa, G. (Gloria); Aranguren, X.L. (Xabier L.); Adney, J. (Josuah R.); Verfaillie, C.M. (Catherine M.)Despite progress in cardiovascular research, a cure for peripheral vascular disease has not been found. We compared the vascularization and tissue regeneration potential of murine and human undifferentiated multipotent adult progenitor cells (mMAPC-U and hMAPC-U), murine MAPC-derived vascular progenitors (mMAPC-VP), and unselected murine BM cells (mBMCs) in mice with moderate limb ischemia, reminiscent of intermittent claudication in human patients. mMAPC-U durably restored blood flow and muscle function and stimulated muscle regeneration, by direct and trophic contribution to vascular and skeletal muscle growth. This was in contrast to mBMCs and mMAPC-VP, which did not affect muscle regeneration and provided only limited and transient improvement. Moreover, mBMCs participated in a sustained inflammatory response in the lower limb, associated with progressive deterioration in muscle function. Importantly, mMAPC-U and hMAPC-U also remedied vascular and muscular deficiency in severe limb ischemia, representative of critical limb ischemia in humans. Thus, unlike BMCs or vascular-committed progenitors, undifferentiated multipotent adult progenitor cells offer the potential to durably repair ischemic damage in peripheral vascular disease patients.
- Multipotent Adult Progenitor Cells Support Lymphatic Regeneration at Multiple Anatomical Levels during Wound Healing and Lymphedema(Springer Nature, 2018) Hendrickx, B. (B.); Dheedene, W. (Wouter); Luttun, A. (Aernout); Beerens, M. (Manu); Himmelreich, U. (Uwe); Dresselaers, T. (Tom); Aranguren, X.L. (Xabier L.); Verfaillie, C.M. (Catherine M.)Lymphatic capillary growth is an integral part of wound healing, yet, the combined efectiveness of stem/progenitor cells on lymphatic and blood vascular regeneration in wounds needs further exploration. Stem/progenitor cell transplantation also emerged as an approach to cure lymphedema, a condition caused by lymphatic system defciency. While lymphedema treatment requires lymphatic system restoration from the capillary to the collector level, it remains undetermined whether stem/ progenitor cells support a complex regenerative response across the entire anatomical spectrum of the system. Here, we demonstrate that, although multipotent adult progenitor cells (MAPCs) showed potential to diferentiate down the lymphatic endothelial lineage, they mainly trophically supported lymphatic endothelial cell behaviour in vitro. In vivo, MAPC transplantation supported blood vessel and lymphatic capillary growth in wounds and restored lymph drainage across skin faps by stimulating capillary and pre-collector vessel regeneration. Finally, human MAPCs mediated survival and functional reconnection of transplanted lymph nodes to the host lymphatic network by improving their (lymph) vascular supply and restoring collector vessels. Thus, MAPC transplantation represents a promising remedy for lymphatic system restoration at diferent anatomical levels and hence an appealing treatment for lymphedema. Furthermore, its combined efcacy on lymphatic and blood vascular growth is an important asset for wound healing.
- In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells(American Society of Hematology, 2007) Uriz, M. (Maialen); Araña, M. (Miriam); Soriano, M. (Mario); Andreu, E.J. (Enrique José); Barajas, M. (Miguel); Luttun, A. (Aernout); Garcia-Verdugo, J.M. (José Manuel); Clavel, C. (C.); Prosper-Cardoso, F. (Felipe); Merino, J. (Juana); Pelacho, B. (Beatriz); Echavarría, A. (Agustín); Abizanda-Sarasa, G. (Gloria); Aranguren, X.L. (Xabier L.); Verfaillie, C.M. (Catherine M.); Moreno, C. (Cristina)Many stem cell types have been shown to differentiate into endothelial cells (ECs); however, their specification to arterial or venous endothelium remains unexplored. We tested whether a specific arterial or venous EC fate could be induced in human multipotent adult progenitor cells (hMAPCs) and AC133 cells (hAC133 ). In vitro, in the presence of VEGF165, hAC133 cells only adopted a venous and microvascular EC phenotype, while hMAPCs differentiated into both arterial and venous ECs, possibly because hMAPCs expressed significantly more sonic hedgehog (Shh) and its receptors as well as Notch 1 and 3 receptors and some of their ligands. Accordingly, blocking either of those pathways attenuated in vitro arterial EC differentiation from hMAPCs. Complementarily, stimulating these pathways by addition of Delta-like 4 (Dll-4), a Notch ligand, and Shh to VEGF165 further boosted arterial differentiation in hMAPCs both in vitro and in an in vivo Matrigel model. These results represent the first demonstration of adult stem cells with the potential to be differentiated into different types of ECs in vitro and in vivo and provide a useful human model to study arteriovenous specification.
- Therapeutic potential of adult progenitor cells in cardiovascular disease(Ashley Publications, 2007) Luttun, A. (Aernout); Prosper-Cardoso, F. (Felipe); Pelacho, B. (Beatriz); Aranguren, X.L. (Xabier L.); Verfaillie, C.M. (Catherine M.)Cardiovascular diseases are responsible for high morbidity/mortality rates worldwide. Advances in patient care have significantly reduced deaths from acute myocardial infarction. However, the cardiac remodeling processes induced after ischaemia are responsible for a worsening in the heart condition, which in many cases ends up in failure. In the last decade, a novel therapy based on stem cell transplantation is being intensively studied in animal models and some stem cell types (i.e., skeletal myoblasts and bone marrow-derived cells) are already being tested in clinical trials. A novel stem cell population isolated from the bone marrow, termed multipotent adult progenitor cells was characterised a few years ago by its ability to differentiate, at the single cell level, towards cells derived from the three embryonic germ layers. Later on, other pluripotent cell populations have been also derived from the bone marrow. In this overview, the authors outline different stem cell sources that have been tested for their cardiovascular potential and put the regenerative potential of multipotent adult progenitor cells in animal models of acute and chronic myocardial infarction into perspective.
- Differentiation of Multipotent Adult Progenitor Cells into Functional Endothelial and Smooth Muscle Cells(Wiley-Blackwell, 2006) Ross, J.J. (John J.); Luttun, A. (Aernout); Prosper-Cardoso, F. (Felipe); Aranguren, X.L. (Xabier L.); Verfaillie, C.M. (Catherine M.)