Fundacion

Publicado en: Nature Communications

1. Arauz S, González-Martín D, Quiroga M, Guillén-García P. Arthroscopic Modified McLaughlin Procedure and Remplissage for Treatment of Simultaneous Reverse Hill-Sachs and Hill-Sachs Lesions. Arthrosc Tech 2022 Jul 14;11(8):e1473-e1478. doi: 10.1016/j.eats.2022.03.038. eCollection 2022 Aug.
2. Campón Chekroun A, Velázquez-Saornil J, Guillén-Vicente I, Sánchez Milá Z, Rodríguez-Sanz D, Romero-Morales C, Fernandez-Jaén T, Garrido González JI, Sánchez-Garrido MÁ, Guillén-García P. Consensus Delphi study on guidelines for the assessment of anterior cruciate ligament injuries in children. World J Orthop 2022 Sep 18;13(9):777-790. doi: 10.5312/wjo.v13.i9.777.
3. Kristen C. Browder, Pradeep Reddy, Mako Yamamoto, Amin Haghani, Isabel Guillen Guillen, Sanjeeb Sahu, Chao Wang, Yosu Luque, Javier Prieto, Lei Shi, Kensaku Shojima, Tomoaki Hishida, Zijuan Lai, Qingling Li, Feroza K. Choudhury, Weng R. Wong, Yuxin Liang, Dewakar Sangaraju, Wendy Sandoval, Concepcion Rodriguez Esteban, Estrella Nuñez Delicado, Pedro Guillen Garcia, Michal Pawlak, Jason A. Vander Heiden, Steve Horvath, Heinrich Jasper & Juan Carlos Izpisua Belmonte. In vivo partial reprogramming alters age-associated molecular changes during physiological aging in mice. Nature Aging 2022, 2: 243-253.
4. Luis Celada O, García-Cota J, Herrero-González H, Martínez-Rodríguez R, Galán-del-Rio F, Rodríguez-Iñigo E, Fernández-Jaén TF, Fortoul-García MP, Guillen-García P, López-Alcorocho JM. Estudio epidemiológico de las lesiones de la Selección Española Absoluta de Futbol durante 2008-2015. Rev.int.med.cienc.act.fis.deporte 2020 (En prensa).
5. Fernandez-Jaén T, Sanz-Zapata F, Cortés JM, Balius-Mata R, Alvarez-Rey G, Garrido-Gonzalez JM, Colmenero-Rolon C, Recio-Alvarez I, Guillen-Garcia P. Proposal for a Clinical Analysis of Patellar Tendon Pathologies: In Search of Efficient Therapeutic Indications. Orthop J Sports Med 2020 Aug 31;8(8):2325967120946312. doi: 10.1177/2325967120946312.
6. Study Group of the Muscle and Tendon System from the Spanish Society of Sports Traumatology; Ramon Balius, Marc Blasi, Carles Pedret, Xavier Alomar, José Peña-Amaro, José A Vega, Ricard Pruna, Jordi Ardèvol, Guillermo Álvarez, Javier de la Fuente, Tomás Fernández-Jaén, Tero A H Järvinen, Gil Rodas. A Histoarchitectural Approach to Skeletal Muscle Injury: Searching for a Common Nomenclature. Orthop J Sports Med 2020 Mar 20;8(3):2325967120909090. doi: 10.1177/2325967120909090.

Publicado en: Nature Communications

Abstract. Identification of the precise molecular pathways involved in oncogene-induced transformation may help us gain a better understanding of tumor initiation and promotion. Here, we demonstrate that SOX2+ foregut epithelial cells are prone to oncogenic transformation upon mutagenic insults, such as KrasG12D and p53 deletion. GFP-based lineage-tracing experiments indicate that SOX2+ cells are the cells-of-origin of esophagus and stomach hyperplasia. Our observations indicate distinct roles for oncogenic KRAS mutation and P53 deletion. p53 homozygous deletion is required for
the acquisition of an invasive potential, and KrasG12D expression, but not p53 deletion, suffices for tumor
formation. Global gene expression analysis reveals secreting factors upregulated in the hyperplasia induced by oncogenic KRAS and highlights a crucial role for the CXCR2 pathway in driving hyperplasia. Collectively, the array of genetic models presented here demonstrate that stratified epithelial cells are susceptible to oncogenic insults, which may lead to a better understanding of tumor initiation and aid in the design of new cancer therapeutics.

Referencia:

Hishida T, Vazquez-Ferrer E, Hishida-Nozaki Y, Sancho-Martinez I, Takahashi Y, Hatanaka F, Wu J, Ocampo A, Reddy P, Wu MZ, Gerken L, Shaw RJ, Rodriguez Esteban C, Benner C, Nakagawa H, Guillen Garcia P, Nuñez Delicado E, Castells A, Campistol JM, Liu GH, Izpisua Belmonte JC. Mutations in Foregut SOX2 + Cells Induce Efficient Proliferation via CXCR2 Pathway. Protein Cell 2019 Jul;10(7):485-495. doi: 10.1007/s13238-019-0630-3. Epub 2019 Apr 30.

Link: https://doi.org/10.1007/s13238-019-0630-3

Publicado en: Nature Communications

Abstract. Pluripotency, the ability to generate any cell type of the body, is an evanescent attribute of embryonic cells. Transitory pluripotent cells can be captured at different time points during embryogenesis and maintained as embryonic stem cells or epiblast stem cells in culture. Since ontogenesis is a dynamic process in both space and time, it seems counterintuitive that these two temporal states represent the full spectrum of organismal pluripotency. Here we show that by modulating
culture parameters, a stem-cell type with unique spatial characteristics and distinct molecular and functional features, designated as region-selective pluripotent stem cells (rsPSCs), can be efficiently obtained from mouse embryos and primate pluripotent stem cells, including humans. The ease of culturing and editing the genome of human rsPSCs offers advantages for regenerative medicine applications. The unique ability of human rsPSCs to generate post-implantation
interspecies chimaeric embryos may facilitate our understanding of early human development and evolution.

Referencia:

Wu J, Okamura D, Li M, Suzuki K, Luo C, Ma L, He Y, Li Z, Benner C, Tamura I, Krause MN, Nery JR, Du T, Zhang Z, Hishida T, Takahashi Y, Aizawa E, Kim NY, Lajara J, Guillen P, Campistol JM, Esteban CR, Ross PJ, Saghatelian A, Ren B, Ecker JR, Izpisua Belmonte JC. An alternative pluripotent state confers interspecies chimaeric competency. Nature. 2015;521:316-21.

Publicado en: Nature Communications

Abstract. Transit-amplifying nephron progenitor cells (NPCs) generate all of the nephrons of the
mammalian kidney during development. Their limited numbers, poor in vitro expansion, and difficult accessibility in humans have slowed basic and translational research into renal
development and diseases. Here, we show that with appropriate 3D culture conditions, it is
possible to support long-term expansion of primary mouse and human fetal NPCs as well as NPCs
derived from human induced pluripotent stem cells (iPSCs). Expanded NPCs maintain genomic
stability, molecular homogeneity, and nephrogenic potential in vitro, ex vivo, and in vivo. Cultured
NPCs are amenable to gene targeting and can form nephron organoids that engraft in vivo,
functionally couple to the host’s circulatory system, and produce urine-like metabolites via
filtration. Together, these findings provide a technological platform for studying human
nephrogenesis, modeling and diagnosing renal diseases, and drug discovery.

Referencia:

Li Z, Araoka T, Wu J, Liao HK, Li M, Lazo M, Zhou B, Sui Y, Wu MZ, Tamura I, Xia Y, Beyret E, Matsusaka T, Pastan I, Rodriguez Esteban C, Guillen I, Guillen P, Campistol JM, Izpisua Belmonte JC. 3D Culture Supports Long-Term Expansion of Mouse and Human Nephrogenic Progenitors. Cell Stem Cell. 2016;6;19:516-529.

Link: http://dx.doi.org/10.1016/j.stem.2016.07.016

Publicado en: Nature Communications

Abstract. In vivo genome editing represents a powerful strategy for both understanding basic biology and treating inherited diseases. However, it remains a challenge to develop universal and efficient in vivo genome-editing tools for tissues that comprise diverse cell types in either a dividing or non-dividing state. Here, we describe a versatile in vivo gene knock-in methodology that enables the targeting of a broad range of mutations and cell types through the insertion of a minigene at an intron of the target gene locus using an intracellularly linearized single homology arm donor. As a proof-of-concept, we focused on a mouse model of prematureaging caused by a dominant point mutation, which is difficult to repair using existing in vivo genome-editing tools. Systemic treatment using our new method ameliorated aging-associated phenotypes and extended animal lifespan, thus highlighting the potential of this methodology for a broad range of in vivo genome-editing applications.

Referencia:

Suzuki K, Yamamoto M, Hernandez-Benitez R, Li Z, Wei C, Devi Soligalla R, Aizawa E, Hatanaka F, Kurita M, Reddy P, Ocampo A, Hishida T, Sakurai M, Nemeth AN, Nuñez Delicado E, Campistol JM, Magistretti P, Guillen P, Rodriguez Esteban C, Gong J, Yuan Y, Gu Y, Liu G-H, López-Otín C, Wu J, Zhang K, Izpisua Belmonte JC. Precise in vivo genome editing via one-homology armed donor mediated intron-targeting gene integration. Cell Res. 2019 Oct;29(10):804-819. doi: 10.1038/s41422-019-0213-0. Epub 2019 Aug 23.

Link: https://doi.org/10.1038/s41422-019-0213-0

Publicado en: Nature Communications

Abstract. Background: We hypothesized that implanting cells in a chondral defect at a density more similar to that of the intact cartilage could induce them to synthesize matrix with the features more similar to that of the uninjured one. Methods: We compared the implantation of different doses of chondrocytes: 1 million (n = 5), 5 million (n = 5), or 5 million mesenchymal cells (n = 5) in the femoral condyle of 15 sheep. Tissue generated by microfracture at the trochlea, and normal cartilage from a nearby region, processed as the tissues resulting from the implantation, were used as references. Histological and molecular (expression of type I and II collagens and aggrecan) studies were performed. Results: The features of the cartilage generated by implantation of mesenchymal cells and elicited by microfractures were similar and typical of a poor repair of the articular cartilage (presence of fibrocartilage, high expression of type I collagen and a low mRNA levels of type II
collagen and aggrecan). Nevertheless, in the samples obtained from tissues generated by implantation of chondrocytes, hyaline-like cartilage, cell organization, low expression rates of type I collagen and high levels of mRNA corresponding to type II collagen and aggrecan were observed. These histological features, show less variability and are more similar to those of the normal cartilage used as control in the case of 5 million cells implantation than when 1 million cells were used.

Conclusions: The implantation of autologous chondrocytes in type I/III collagen membranes at high density could be a promising tool to repair articular cartilage.

Referencia:

Guillén-García P, Rodríguez-Iñigo E, Aráuz S, Guillén-Vicente M, Guillén-Vicente I, Caballero-Santos R, Ramos-Martín T, Fernández-Jaén T, Abelow S, López-Alcorocho JM. Nuestra experiencia con la técnica de implante de condrocitos autólogos para el tratamiento de lesiones condrales: resultados de 50 pacientes a 2 años de seguimiento. Revista Española de Artroscopia y Cirugía Articular 2015;22:120-125

Publicado en: Nature Communications

Abstract. El tratamiento de los defectos del cartílago articular representa un reto para la cirugía ortopédica actual, debido a que es un tejido aneural, avascular y alinfático, que tras una lesión no cura espontáneamente. A lo largo de los años se han ido desarrollando una serie de técnicas para tratar esos defectos, desde la estimulación de la médula ósea mediante microfracturas, pasando por el injerto de cartílago tanto autólogo como alogénico, hasta llegar al tratamiento con células. La terapia celular aplicada al cartílago nace en 1994 con la utilización de condrocitos autólogos en medio líquido, y desde entonces, ha ido evolucionando hasta llegar al empleo de un transportador (carrier) para llevar las células al lugar donde está el defecto cartilaginoso. La última evolución de esta técnica es el implante de condrocitos autólogos a alta densidad utilizando una membrana de colágeno como transportador. El implante de condrocitos autólogos es actualmente la única capaz de proporcionar una réplica del tejido original, consiguiendo unos resultados buenos o excelentes en más del 80% de los casos. Sin emaborgo, para su empleo se requieren dos cirugías: una para la toma de la biopsia de donde se van a aislar los condrocitos y otra para el implante de las células. Por este motivo, se han investigado otras alternativas como fuente de células terapéuticas. La primera ha sido el empleo de células madre mesenquimales de distintos orígenes, que aunque prometedoras in vitro, por el momento no han rendido ningún resultado clínico. Ante estos resultados, se han comenzado las investigaciones con otra clase de células, las células pluripotenciales inducidas que pueden obtenerse de cualquier tejido del organismo y que, por tanto, podrían ser alternativa idónea a los condrocitos. Los estudios con estas células, así como la investigación de nuevos biomateriales, abren las puertas a un futuro esperanzador en el trata,iento de las lesiones del cartílago articular.

Referencia:

Lopez-Alcorocho JM, PRodriguez-Iñigo E, Guillen-Vicente I, Guillen-Vicente M, Fernández-Jaén TF, Maestro Fernández A, Guillén-García P. Presente y Futuro del Implante de Condrocitos Autólogos para el tratamiento de las lesiones del cartílago articular. Journal of Cartilage Disease 2016;2: 4-13.

Publicado en: Nature Communications

Abstract. To study if a culture of chondrocytes can be obtained from pathologic hyaline cartilage (PHC) fragments. Design. Twenty-five men and 9 women with osteochondritis dissecans (OCD) in 11 cases, arthrosis in 13 patients, and trauma in the remaining 10 cases were included. The PHC fragments and a small sample of the next healthy cartilage were extracted by arthroscopy. According to the appearance, the PHC samples were divided into fixed (3 cases), flapped (6 patients), or loose bodies (25 cases), depending on the attachment degree of the cartilage to the subchondral bone. Approximately half
of each pathologic sample and the whole healthy one were digested to isolate the cells trying to establish the cell culture.
Results. We were able to establish a cell culture in 7 out of 34 (20.6%) PHC samples (positive samples), whereas in the remaining 27 (79.4%) no cell growth was observed (negative samples). Most of the negative samples were loose bodies (P = 0.005) taken from patients with OCD or arthrosis (P = 0.001) with an evolution time of more than 1 year (P < 0.001).
The best binary logistic regression model (P < 0.001) showed that the only factor affecting the establishment of cell culture was the evolution time (P = 0.044). Conclusion. It is possible to culture chondrocytes from osteochondral fragments if they are traumatic, within a year of injury and not from fragments due to arthrosis or OCD.

Referencia:

Guillén-García P, Rodríguez-Iñigo E, Guillén-Vicente I, Guillén-Vicente M, Fernández-Jaén T, Concejero V, Val D, Maestro A, Abelow S, López-Alcorocho JM. Viability of Pathologic Cartilage Fragments as a Source for Autologous Chondrocyte Cultures. Cartilage. 2016;7:149-56.