Silvia Díaz‐Prado

Instituto de Investigación Biomédica de A Coruña

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Francisco J. Blanco

Complexo Hospitalario Universitario A Coruña

Isaac Fuentes‐Boquete

Universidade da Coruña

Tamara Hermida‐Gómez

Instituto de Investigación Biomédica de A Coruña

Clara Sanjurjo‐Rodríguez

Universidade da Coruña

Francisco Javier de Toro Santos

Complexo Hospitalario Universitario A Coruña

R. Castro-Viñuelas

KU Leuven

María Piñeiro-Ramil

Universidade da Coruña

Silvia Rodríguez-Fernández

Instituto de Investigación Biomédica de A Coruña

Emma Muiños‐López

Clinica Universidad de Navarra

E. Rendal

Instituto de Investigación Biomédica de A Coruña

Cooperative Institutions

Universidade da Coruña

Instituto de Investigación Biomédica de A Coruña

Complexo Hospitalario Universitario A Coruña

Servicio Gallego de Salud

Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine

Centro de Investigación Biomédica en Red

Hospital San Juan de la Cruz

Instituto de Salud Carlos III

Centro de Investigacion Principe Felipe

Centre for Biomedical Network Research on Rare Diseases

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Induced pluripotent stem cells for cartilage repair: current status and future perspectives

European Cells and Materials (2018)

R. Castro-Viñuelas Clara Sanjurjo‐Rodríguez María Piñeiro-Ramil Tamara Hermida‐Gómez IM Fuentes-Boquete

The establishment of cartilage regenerative medicine is an important clinical issue, but the search for cell sources able to restore cartilage integrity proves to be challenging.Human mesenchymal stromal cells (MSCs) are prone to form epiphyseal or hypertrophic cartilage and have an age-related limited proliferation.On the other hand, it is difficult to obtain functional chondrocytes from human embryonic stem cells (ESCs).Moreover, the ethical issues associated with human ESCs are an additional disadvantage of using such cells.Since their discovery in 2006, induced pluripotent stems cells (iPSCs) have opened many gateways to regenerative medicine research, especially in cartilage tissue engineering therapies.iPSCs have the capacity to overcome limitations associated with current cell sources since large numbers of autologous cells can be derived from small starting populations.Moreover, problems associated with epiphyseal or hypertrophiccartilage formation can be overcome using iPSCs.iPSCs emerge as a promising cell source for treating cartilage defects and have the potential to be used in the clinical field.For this purpose, robust protocols to induce chondrogenesis, both in vitro an in vivo, are required.This review summarises the recent progress in iPSC technology and its applications for cartilage repair.

Regenerative Medicine

Chondrogenesis

10.22203/ecm.v036a08

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Citations (76)

Cartilage tissue engineering: adult human mesenchymal stromal cells and collagen biomaterials

Osteoarthritis and Cartilage (2014)

Clara Sanjurjo‐Rodríguez Adela Helvia Martínez Sánchez Tamara Hermida‐Gómez I.M. Fuentes Julia Buján

Chondrogenesis

Aggrecan

10.1016/j.joca.2014.02.286

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Citations (2)

Generation and characterization of human induced pluripotent stem cells (iPSCs) from hand osteoarthritis patient-derived fibroblasts

Scientific Reports (2020)

R. Castro-Viñuelas Clara Sanjurjo‐Rodríguez María Piñeiro-Ramil Tamara Hermida‐Gómez Silvia Rodríguez-Fernández

Knowledge and research results about hand osteoarthritis (hOA) are limited due to the lack of samples and animal models of the disease. Here, we report the generation of two induced pluripotent stem cell (iPSC)-lines from patients with radiographic hOA. Furthermore, we wondered whether these iPSC-lines carried single nucleotide polymorphisms (SNPs) within genes that have been associated with hOA. Finally, we performed chondrogenic differentiation of the iPSCs in order to prove their usefulness as cellular models of the disease. We performed a non-integrative reprogramming of dermal fibroblasts obtained from two patients with radiographic rhizarthrosis and non-erosive hOA by introducing the transcriptional factors Oct4, Sox2, Klf4 and c-Myc using Sendai virus. After reprogramming, embryonic stem cell-like colonies emerged in culture, which fulfilled all the criteria to be considered iPSCs. Both iPSC-lines carried variants associated with hOA in the four studied genes and showed differences in their chondrogenic capacity when compared with a healthy control iPSC-line. To our knowledge this is the first time that the generation of iPSC-lines from patients with rhizarthrosis and non-erosive hOA is reported. The obtained iPSC-lines might enable us to model the disease in vitro, and to deeper study both the molecular and cellular mechanisms underlying hOA.

10.1038/s41598-020-61071-6

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Citations (42)

Evolutionarily conserved proteins MnmE and GidA catalyze the formation of two methyluridine derivatives at tRNA wobble positions

Nucleic Acids Research (2009)

Ismaïl Moukadiri Silvia Díaz‐Prado Julio Piera Adrián Velazquez‐Campoy Glenn R. Björk

The wobble uridine of certain bacterial and mitochondrial tRNAs is modified, at position 5, through an unknown reaction pathway that utilizes the evolutionarily conserved MnmE and GidA proteins. The resulting modification (a methyluridine derivative) plays a critical role in decoding NNG/A codons and reading frame maintenance during mRNA translation. The lack of this tRNA modification produces a pleiotropic phenotype in bacteria and has been associated with mitochondrial encephalomyopathies in humans. In this work, we use in vitro and in vivo approaches to characterize the enzymatic pathway controlled by the Escherichia coli MnmE•GidA complex. Surprisingly, this complex catalyzes two different GTP- and FAD-dependent reactions, which produce 5-aminomethyluridine and 5-carboxymethylamino-methyluridine using ammonium and glycine, respectively, as substrates. In both reactions, methylene-tetrahydrofolate is the most probable source to form the C5-methylene moiety, whereas NADH is dispensable in vitro unless FAD levels are limiting. Our results allow us to reformulate the bacterial MnmE•GidA dependent pathway and propose a novel mechanism for the modification reactions performed by the MnmE and GidA family proteins.

Wobble base pair

10.1093/nar/gkp762

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Citations (105)

Characterization of Human GTPBP3, a GTP-Binding Protein Involved in Mitochondrial tRNA Modification

Molecular and Cellular Biology (2008)

Magda Villarroya Silvia Díaz‐Prado Juan M. Esteve Miguel A. Soriano Carmen Aguado

Human GTPBP3 is an evolutionarily conserved, multidomain protein involved in mitochondrial tRNA modification. Characterization of its biochemical properties and the phenotype conferred by GTPBP3 inactivation is crucial to understanding the role of this protein in tRNA maturation and its effects on mitochondrial respiration. We show that the two most abundant GTPBP3 isoforms exhibit moderate affinity for guanine nucleotides like their bacterial homologue, MnmE, although they hydrolyze GTP at a 100-fold lower rate. This suggests that regulation of the GTPase activity, essential for the tRNA modification function of MnmE, is different in GTPBP3. In fact, potassium-induced dimerization of the G domain leads to stimulation of the GTPase activity in MnmE but not in GTPBP3. The GTPBP3 N-terminal domain mediates a potassium-independent dimerization, which appears as an evolutionarily conserved property of the protein family, probably related to the construction of the binding site for the one-carbon-unit donor in the modification reaction. Partial inactivation of GTPBP3 by small interfering RNA reduces oxygen consumption, ATP production, and mitochondrial protein synthesis, while the degradation of these proteins slightly increases. It also results in mitochondria with defective membrane potential and increased superoxide levels. These phenotypic traits suggest that GTPBP3 defects contribute to the pathogenesis of some oxidative phosphorylation diseases.

10.1128/mcb.00946-08

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Usefulness of Mesenchymal Cell Lines for Bone and Cartilage Regeneration Research

International Journal of Molecular Sciences (2019)

María Piñeiro-Ramil Clara Sanjurjo‐Rodríguez R. Castro-Viñuelas Silvia Rodríguez-Fernández Isaac Fuentes‐Boquete

The unavailability of sufficient numbers of human primary cells is a major roadblock for in vitro repair of bone and/or cartilage, and for performing disease modelling experiments. Immortalized mesenchymal stromal cells (iMSCs) may be employed as a research tool for avoiding these problems. The purpose of this review was to revise the available literature on the characteristics of the iMSC lines, paying special attention to the maintenance of the phenotype of the primary cells from which they were derived, and whether they are effectively useful for in vitro disease modeling and cell therapy purposes. This review was performed by searching on Web of Science, Scopus, and PubMed databases from 1 January 2015 to 30 September 2019. The keywords used were ALL = (mesenchymal AND (“cell line” OR immortal*) AND (cartilage OR chondrogenesis OR bone OR osteogenesis) AND human). Only original research studies in which a human iMSC line was employed for osteogenesis or chondrogenesis experiments were included. After describing the success of the immortalization protocol, we focused on the iMSCs maintenance of the parental phenotype and multipotency. According to the literature revised, it seems that the maintenance of these characteristics is not guaranteed by immortalization, and that careful selection and validation of clones with particular characteristics is necessary for taking advantage of the full potential of iMSC to be employed in bone and cartilage-related research.

Chondrogenesis

Unavailability

10.3390/ijms20246286

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Citations (21)

Modification of the wobble uridine in bacterial and mitochondrial tRNAs reading NNA/NNG triplets of 2-codon boxes

RNA Biology (2014)

M.‐Eugenia Armengod Salvador Meseguer Magda Villarroya Silvia Díaz‐Prado Ismaïl Moukadiri

Posttranscriptional modification of the uridine located at the wobble position (U34) of tRNAs is crucial for optimization of translation. Defects in the U34 modification of mitochondrial-tRNAs are associated with a group of rare diseases collectively characterized by the impairment of the oxidative phosphorylation system. Retrograde signaling pathways from mitochondria to nucleus are involved in the pathophysiology of these diseases. These pathways may be triggered by not only the disturbance of the mitochondrial (mt) translation caused by hypomodification of tRNAs, but also as a result of nonconventional roles of mt-tRNAs and mt-tRNA-modifying enzymes. The evolutionary conservation of these enzymes supports their importance for cell and organismal functions. Interestingly, bacterial and eukaryotic cells respond to stress by altering the expression or activity of these tRNA-modifying enzymes, which leads to changes in the modification status of tRNAs. This review summarizes recent findings about these enzymes and sets them within the previous data context.

Wobble base pair

10.4161/15476286.2014.992269

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Citations (66)

Differentiation of human mesenchymal stromal cells cultured on collagen sponges for cartilage repair.

PubMed (2016)

Clara Sanjurjo‐Rodríguez Adela Helvia Martínez-Sánchez Tamara Hermida‐Gómez Isaac Fuentes‐Boquete Silvia Díaz‐Prado

The aim of this study was to evaluate proliferation and chondrogenic differentiation of human bone-marrow mesenchymal stromal cells (hBMSCs) cultured on collagen biomaterials.hBMSCs were seeded on five different collagen (Col) sponges: C1C2 (types I and II Col), C1C2HS (types I and II Col plus heparan sulphate (HS)), C1C2CHS (types I and II Col plus chondroitin sulphate (CHS)), C1-OLH3 (type I Col plus low molecular weight heparin) and C1CHS (type I Col plus CHS). The resulting constructs were analyzed by histological and immunohistochemical staining, molecular biology and electron microscopy. Col released into culture media was measured by a dye-binding method Results: hBMSCs on biomaterials C1C2, C1C2HS and C1C2CHS had more capacity to attach, proliferate and synthesize Col II and proteoglycans in the extracellular matrix (ECM) than on C1-OLH3 and C1CHS. The presence of aggrecan was detected only at the gene level. Total Col liberated by the cells in the supernatants in all scaffold cultures was detected. The level of Col I in the ECM was lower in C1-OLH3 and that of Col II was highest in C1C2 and C1C2HS. Electron microscopy showed differently shaped cells, from rounded to flattened, in all constructs. Col fibers in bundles were observed in C1C2CHS by transmission electron microscopy.The results show that Col I and Col II (C1C2, C1C2HS and C1C2CHS) biomaterials allowed cell proliferation and chondrogenic-like differentiation of hBMSCs at an early stage. Constructs cultured on C1C2HS and C1C2CHS showed better cartilage-like phenotype than the other ones.

Chondrogenesis

Aggrecan

Type II collagen

Type I collagen

Matrix (chemical analysis)

10.14670/hh-11-754

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Generation of a human control iPS cell line (ESi080‐A) from a donor with no rheumatic diseases

Stem Cell Research (2019)

R. Castro-Viñuelas Clara Sanjurjo‐Rodríguez María Piñeiro-Ramil Silvia Rodríguez-Fernández Isaac Fuentes‐Boquete

Here, we report the establishment of the human iPS cell line N1-FiPS4F#7 generated from skin cells of a patient with no rheumatic diseases, thus obtaining an appropriate control iPS cell line for researchers working in the field of rheumatic diseases. The reprogramming factors Oct4, Sox2, Klf4 and c-Myc were introduced using a non-integrating reprogramming strategy involving Sendai Virus.

Reprogramming

KLF4

Sendai virus

10.1016/j.scr.2019.101683

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Citations (4)

Can a checklist protocol improve limb lengthening?

Journal of Limb Lengthening & Reconstruction (2022)

Monica Paschoal Nogueira João Pedro Osseti Felicio Silva Ana Maria Ferreira Paccola Silvia Díaz‐Prado

Background: In recent years, hexapodal external fixators and telescopic nails have improved the accuracy of limb lengthening and correction of deformities. However, careful follow-up in the postoperative period is extremely important; complications are still frequent and directly interfere with patient's outcome. Aims and Objectives: We have developed a follow-up limb lengthening reconstruction checklist. Materials and Methods: Like a flight checklist, professionals systematically record relevant data in every postoperative visit, to improve clinical management during distraction and consolidating phases. Results: LLR-Checklist was used in 53 consecutive patients, from 2006 to 2020. Average age was 11 (2-45) years. A pattern was found in the 18 patients with fibular hemimelia in relation to the use of antibiotics. Superficial infection was common. 21% of patients had delayed ossification in the regenerate. 25% of patients had nerve injuries; 9,4% of them had nerve decompression, all had total recovery. Contractures and pain improved with physical therapy. Conclusion: This checklist can improve quality in the treatment and is a valuable teaching tool for young practitioners.

Muscle contracture

10.4103/jllr.jllr_43_21

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Citations (1)