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Leuven, Belgium

Quattrocelli M.,Catholic University of Leuven | Swinnen M.,Catholic University of Leuven | Giacomazzi G.,Catholic University of Leuven | Camps J.,Catholic University of Leuven | And 12 more authors.
Journal of Clinical Investigation | Year: 2015

Conditions such as muscular dystrophies (MDs) that affect both cardiac and skeletal muscles would benefit from therapeutic strategies that enable regeneration of both of these striated muscle types. Protocols have been developed to promote induced pluripotent stem cells (iPSCs) to differentiate toward cardiac or skeletal muscle; however, there are currently no strategies to simultaneously target both muscle types. Tissues exhibit specific epigenetic alterations; therefore, source-related lineage biases have the potential to improve iPSC-driven multilineage differentiation. Here, we determined that differential myogenic propensity influences the commitment of isogenic iPSCs and a specifically isolated pool of mesodermal iPSC-derived progenitors (MiPs) toward the striated muscle lineages. Differential myogenic propensity did not influence pluripotency, but did selectively enhance chimerism of MiP-derived tissue in both fetal and adult skeletal muscle. When injected into dystrophic mice, MiPs engrafted and repaired both skeletal and cardiac muscle, reducing functional defects. Similarly, engraftment into dystrophic mice of canine MiPs from dystrophic dogs that had undergone TALEN-mediated correction of the MD-associated mutation also resulted in functional striatal muscle regeneration. Moreover, human MiPs exhibited the same capacity for the dual differentiation observed in murine and canine MiPs. The findings of this study suggest that MiPs should be further explored for combined therapy of cardiac and skeletal muscles. Source

Chen Y.,Chongqing Medical University | Chen Y.,Stem Cell Institute Leuven | Verfaillie C.M.,Stem Cell Institute Leuven
Liver International | Year: 2014

MicroRNAs are a class of small non-coding RNAs involved in the transcriptional and post-transcriptional regulation of gene expression. The function of miRNAs in liver disease including hepatocellular carcinoma (HCC), hepatitis, and alcoholic liver disease, have been widely studied and extensively reviewed. Increasing evidence demonstrates that miRNAs also play a critical role in normal liver development and in the fine-tuning of fundamental biological liver processes. In this review, we highlight the most recent findings on the role of miRNAs in liver specification and differentiation, liver cell development, as well as in the many metabolic functions of the liver, including glucose, lipid, iron and drug metabolism. These findings demonstrate an important role of miRNAs in normal liver development and function. Further researches will be needed to fully understand how miRNAs regulate liver generation and metabolic function, which should then lead to greater insights in liver biology and perhaps open up the possibility to correct errors that cause liver diseases or metabolic disorders. © 2014 John Wiley and Sons A/S. Source

Quattrocelli M.,Stem Cell Institute Leuven | Costamagna D.,Stem Cell Institute Leuven | Giacomazzi G.,Stem Cell Institute Leuven | Camps J.,Stem Cell Institute Leuven | And 2 more authors.
Cell Death and Disease | Year: 2014

Somatic stem cells hold attractive potential for the treatment of muscular dystrophies (MDs). Mesoangioblasts (MABs) constitute a myogenic subset of muscle pericytes and have been shown to efficiently regenerate dystrophic muscles in mice and dogs. In addition, HLA-matched MABs are currently being tested in a phase 1 clinical study on Duchenne MD patients (EudraCT #2011-000176-33). Many reports indicate that the Notch pathway regulates muscle regeneration and satellite cell commitment. However, little is known about Notch-mediated effects on other resident myogenic cells. To possibly potentiate MAB-driven regeneration in vivo, we asked whether Notch signaling played a pivotal role in regulating MAB myogenic capacity. Through different approaches of loss- and gain-of-function in murine and human MABs, we determined that the interplay between Delta-like ligand 1 (Dll1)-activated Notch1 and Mef2C supports MAB commitment in vitro and ameliorates engraftment and functional outcome after intra-arterial delivery in dystrophic mice. Furthermore, using a transgenic mouse model of conditional Dll1 deletion, we demonstrated that Dll1 ablation, either on the injected cells, or on the receiving muscle fibers, impairs MAB regenerative potential. Our data corroborate the perspective of advanced combinations of cell therapy and signaling tuning to enhance therapeutic efficaciousness of somatic stem cells. © 2014 Macmillan Publishers Limited. All rights reserved. Source

Quattrocelli M.,Stem Cell Institute Leuven | Thorrez L.,Stem Cell Institute Leuven | Thorrez L.,Future Health | Thorrez L.,The Interdisciplinary Center | And 2 more authors.
Recent Patents on Drug Delivery and Formulation | Year: 2013

Pluripotent stem cells hold unprecedented potential for regenerative medicine, disease modeling and drug screening. Embryonic stem cells (ESCs), standard model for pluripotency studies, have been recently flanked by induced pluripotent stem cells (iPSCs). iPSCs are obtained from somatic cells via epigenetic and transcriptional reprogramming, overcoming ESC-related ethical issues and enabling the possibility of donor-matching pluripotent cell lines. Since the European Court of Justice banned patents involving embryo disaggregation to generate human ESCs, iPSCs can now fuel the willingness of European companies to invest in treatments based on stem cells. Moreover, iPSCs share many unique features of ESCs, such as unlimited self-renewal potential and broad differentiation capability, even though iPSCs seem more susceptible to genomic instability and display epigenetic biases as compared to ESCs. Both ESCs and iPSCs have been intensely investigated for cardiomyocyte production and cardiac muscle regeneration, both in human and animal models. In vitro and in vivo studies are continuously expanding and refining this field via genetic manipulation and cell conditioning, trying to achieve standard and reproducible products, eligible for clinical and biopharmaceutical scopes. This review focuses on the recently growing body of patents, concerning technical advances in production, expansion and cardiac differentiation of ESCs and iPSCs © 2013 Bentham Science Publishers. Source

Nageshappa S.,Center for Human Genetics | Carromeu C.,University of California at San Diego | Trujillo C.A.,University of California at San Diego | Mesci P.,University of California at San Diego | And 24 more authors.
Molecular Psychiatry | Year: 2016

Increased dosage of methyl-CpG-binding protein-2 (MeCP2) results in a dramatic neurodevelopmental phenotype with onset at birth. We generated induced pluripotent stem cells (iPSCs) from patients with the MECP2 duplication syndrome (MECP2dup), carrying different duplication sizes, to study the impact of increased MeCP2 dosage in human neurons. We show that cortical neurons derived from these different MECP2dup iPSC lines have increased synaptogenesis and dendritic complexity. In addition, using multi-electrodes arrays, we show that neuronal network synchronization was altered in MECP2dup-derived neurons. Given MeCP2 functions at the epigenetic level, we tested whether these alterations were reversible using a library of compounds with defined activity on epigenetic pathways. One histone deacetylase inhibitor, NCH-51, was validated as a potential clinical candidate. Interestingly, this compound has never been considered before as a therapeutic alternative for neurological disorders. Our model recapitulates early stages of the human MECP2 duplication syndrome and represents a promising cellular tool to facilitate therapeutic drug screening for severe neurodevelopmental disorders. © 2016 Macmillan Publishers Limited All rights reserved. Source

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