FUNDACION DR. PEDRO GUILLEN

Publicado en: Nature Communications

Abstract. Accumulating evidence indicates an association between the circadian clock and the aging process. However, it remains elusive whether the deregulation of circadian clock proteins underlies stem cell aging and whether they are targetable for the alleviation of aging-associated syndromes. Here, we identified a transcription factor-independent role of CLOCK, a core component of the molecular circadian clock machinery, in counteracting human mesenchymal stem cell (hMSC) decay. CLOCK expression was
decreased during hMSC aging. In addition, CLOCK deficiency accelerated hMSC senescence, whereas the overexpression of CLOCK, even as a transcriptionally inactive form, rejuvenated physiologically and pathologically aged hMSCs. Mechanistic studies revealed that CLOCK formed complexes with nuclear lamina proteins and KAP1, thus maintaining heterochromatin architecture and stabilizing repetitive genomic sequences. Finally, gene therapy with lentiviral vectors encoding CLOCK promoted cartilage
regeneration and attenuated age-related articular degeneration in mice. These findings demonstrate a noncanonical role of CLOCK in stabilizing heterochromatin, promoting tissue regeneration, and mitigating aging-associated chronic diseases.

Referencia:

Liang C, Liu Z, Song M, Li W, Wu Z, Wang Z, Wang Q, Wang Si, Yan K, Sun L, Hishida T, Cai Y, Izpisua Belmonte JC, Guillen P, Chan P, Zhou Q, Zhang W, Qu J, Liu GH. Stabilization of heterochromatin by CLOCK promotes stem cell rejuvenation and cartilage regeneration. Cell Res 2020 Jul;31(2):187-205. doi: 10.1038/s41422-020-0385-7

Link: https://doi.org/10.1038/s41422-020-0385-7

Publicado en: Nature Communications

Abstract. Background. Ligamentization has been accepted in Anterior Cruciate Ligament (ACL)
surgery. The purpose of this study is to evaluate ligamentization of different allografts
and autografts used as plasties through histological and type I collagen (COL1), tenascin
(TEN) and elastin (ELA) expression analysis.
Methods. Prospective study of patients who underwent ACL reconstruction with at least
1-year follow-up. Biopsies were taken by arthroscopy and tissue sections were stained with
hematoxilin-eosin and Masson’s trichrome. Relative COL1, TEN and ELA expression was
studied by RT-PCR. Hamstring tendon and intact ACL biopsies were used as controls.
Results. Eleven patients with a mean age of 36.6 ± 12.0 years were included. In 9 cases,
ACL reconstruction was carried-out with autologous hamstring tendons while in the 2
remaining patients ACL was reconstructed using an achilles allograft. COL1, TEN and
ELA expression of plasties was significantly different to ACL but similar to hamstring
tendon. Histological analysis showed a dense fibroconnective tissue with cells similar to
tenocytes, which could not be classified neither as a tendon nor as a ligament.
Conclusions. An ACL plasty, independently of its origin (autologous hamstring or allogeneic
achilles) does not become a ligament, at least in our study period (5 years) but it does
maintain ACL functionality.

Referencia:

Guillén-Vicente I, López-Alcorocho JM, Salvador-Marín J, Rodríguez-Iñigo E, Díaz-Motola G, Fernández-Jaén TF, Ibáñez E, Guillén-García P. Histology and type I collagen, tenascin and elastin expression in autologous and allogeneic anterior cruciate ligamentoplasties. Muscle, Ligaments and Tendons Journal 2020 10 (3):473-480.

Publicado en: Nature Communications

Abstract. En este trabajo se estudió la evolución clínica de pacientes con roturade tendón del bíceps braquial tratados mediante reconstrucción quirúrgica según nuestra propiatécnica de doble incisión.Pacientes: Se incluyó a 20 pacientes (21 casos) de rotura de tendón del bíceps braquial trata-dos mediante nuestra propia técnica quirúrgica de doble abordaje modificada, consistente en2 incisiones mínimas. La evaluación funcional se determinó mediante la escala Mayo Elbow Per-formance Score, la fuerza muscular se determinó con el cuestionario Medical Research Councily el dolor mediante la Escala Analógica Visual a los 12 meses de seguimiento. Se determinó elrango de movilidad midiendo los grados de flexión y extensión.Resultados: Un a˜no después de la cirugía todos los pacientes habían vuelto al deporte al mismonivel que tenían previamente. La puntuación de Escala Analógica Visual fue de 1,90 ± 0,89(media ± desviación estándar) y la mediana de la escala Mayo Elbow Performance Score de 90(mínimo-máximo: 80-100). Del total, 16 (76,2%) presentaron la máxima puntuación en la escalaMedical Research Council (puntuación 5), mientras que 5 casos (23,81%) tuvieron una puntaciónde 4+. La media de extensión fue de 136,67◦(IC 95%: 134,14◦-139,19◦) y −7,38◦de flexión(IC 95%: [−10,04◦]-[−4,72◦]).

Referencia:

Ibánez E, Araiza E, Rodríguez-Iñigo E, Guillén-García P, López-Alcorocho JM. Reparación anatómica de las lesiones del tendón distal del bíceps braquial utilizando la técnica quirúrgica de doble incisión. Revista Española de Cirugía Ortopédica y Traumatología 2021 Feb 25;S1888-4415(21)00005-9. doi: 10.1016/j.recot.2020.10.005.

Link: https://doi.org/10.1016/j.recot.2020.10.005

Publicado en: Nature Communications

Abstract. Bilateral knee chondral defects can be treated in one or two surgical acts.
Objectives: To study clinical outcome of patients with bilateral knee chondral defects treated with
High-Density Autologous Chondrocyte Implantation (HD-ACI) during the same surgery.
Methods: Study on eight patients (4 women and 4 men) with chondral defects in both knees
treated with HD-ACI during the same surgical act. Patients were evaluated 2, 6, 12 and 24 months
post-op for treatment safety and efficacy: visual analogic scale (VAS) for pain, International Knee
Documentation Committee (IKDC) for subjective patient’s perception of both knees and EuroQol
five-dimensional five-level questionnaire (EQ-5D-5 L) for quality of life. Integrity of neoformed
tissue at 12 and 24-month follow-up was assessed by the magnetic resonance observation of
cartilage repair tissue (MOCART) score.
Results: VAS decreased from baseline to 24 months from a median of 8 (6 – 9) to a median of 0 (0
– 5) ( P < .001). IKDC increased from a median value of 39.0 (17.2 – 48.3) in the basal visit to a
median of 83.7 (24.0 – 98.0) in the 24-month visit ( P < .001). EQ-5D-5 L decreased at 2 months
post-op and increased throughout the follow-up visits thereafter, needing 24 months after surgery
to reach a value higher than the basal one. Median MOCART at 12 months was 80.3 (58.0 – 89.7)
and 81.3 (54.0 – 89.9) at 24 months.

Referencia:

Guillén-Vicente I, López-Alcorocho JM, Rodríguez-Iñigo E, Guillén-Vicente M, Fernández-Jaén TF, Cortés JM, Abelow S, Guillén-García P. High-Density Autologous Chondrocyte Implantation (HD-ACI) in patients with bilateral knee chondral defects. Journal of Cartilage & Joint Preservation TM 1 (2021) 100013

Link: https://doi.org/10.1016/j.jcjp.2021.100013

Publicado en: Nature Communications

Abstract. Mammals have limited regenerative capacity, whereas some vertebrates, like fish and salamanders, are able to regenerate their organs efficiently. The regeneration in these species depends on cell dedifferentiation followed by proliferation. We generate a mouse model that enables the inducible
expression of the four Yamanaka factors (Oct-3/4, Sox2, Klf4, and c-Myc, or 4F) specifically in
hepatocytes. Transient in vivo 4F expression induces partial reprogramming of adult hepatocytes
to a progenitor state and concomitantly increases cell proliferation. This is indicated by reduced
expression of differentiated hepatic-lineage markers, an increase in markers of proliferation and
chromatin modifiers, global changes in DNA accessibility, and an acquisition of liver stem and
progenitor cell markers. Functionally, short-term expression of 4F enhances liver regenerative
capacity through topoisomerase2-mediated partial reprogramming. Our results reveal that liverspecific 4F expression in vivo induces cellular plasticity and counteracts liver failure, suggesting
that partial reprogramming may represent an avenue for enhancing tissue regeneration.

Referencia:

Hishida T, Yamamoto M, Hishida-Nozaki Y, Shao C, Huang L, Wang C, Shojima K, Xue Y, Hang Y, Shokhirev M, Memczak S, Kumar Sahu S, Hatanaka F, Rabadan Ros R, Maxwell MB, Chavez J, Shao Y, Liao HK, Martinez-Redondo P, Guillen-Guillen I, Hernandez-Benitez R, Rodriguez Esteban C, Qu J, Holmes MC, Yi F, Hickey RD, Guillen Garcia P, Nuñez Delicado E, Castells A, Campistol JM, Yu Y, Hargreaves DC, Asai A, Reddy P, Liu GH, Izpisua Belmonte JC. In vivo partial cellular reprogramming enhances liver plasticity and regeneration. Cell Rep. 2022 Apr 26;39(4):110730. doi: 10.1016/j.celrep.2022.110730.

Link: http://creativecommons.org/licenses/by/4.0/

Publicado en: Nature Communications

Abstract. To study clinical outcome of patients with bilateral ankle chondral defects treated with High-Density
Autologous Chondrocyte Implantation (HD-ACI) in the same surgical act.
Cases presentation: Two men (27 and 48 years-old) with chondral defects in both ankles evidenced by MRI. Chondral
lesions were treated with HD-ACI in the same surgical act and anesthesia, consecutively. Patients were evaluated
2, 6 and 12 months after surgery to check for treatment safety and efficacy. Pain, evaluated by the Visual
Analogic Scale (VAS), decreased from very high values (8.5 – 9) to normal or almost scores one year after surgery (0-1). Ankle functionality measured by the American Orthopedic Foot & Ankle Society score (AOFAS) and quality of life evaluated by the EuroQol five-dimensional five-level questiionnaire (EQ-5D-5L) behaved similarly to pain. Thus, both parameters increased and/or slightly decreased at 2 months (AOFAS socre: 90 and 89; EQ-5D-5L score: 0.89 and 0.91). MRI from both ankles revelaed that chondral defects were filled with a material of similar aspect to the surrounding cartilage.

Referencia:

Guillen-Vicente I, Lopez-Alcorocho JM, Rodríguez-Iñigo E, Navarro R, Guillén-Vicente M, Fernández-Jaen T, Guillén-García P. High density autologous chondrocyte implantation for the treatment of bilateral ankle cartilage defects: Report of two cases. Foot and ankle surgery: Techniques reports and cases 2 (2022) 100218

Link: https://doi.org/10.1016/j.fastrc.2022.100218

Publicado en: Nature Communications

Abstract. In this work we describe the use of high-density autologous chondrocyte implantation
(HD-ACI) to treat 2 patients with chondral defects in the hip.
Case Presentation: Two male, 35- and 37-year-old, with chondral lesions and femoroacetabular
impingement (FAI) were included. Chondrocytes were isolated expanded in vitro and then implanted
at a density of 5 million cells per cm 2 onto a type I/III porcine collagen membrane. None
of the patients had surgery-derived complications. Pain disappeared in both cases at 6 months
after surgery and was maintained until follow-up end (36 months). International Hip Outcome
Tool (iHOT) score increased at 6 and 12 months and then leveled off until month 36.Three-year
arthro-MRI showed the cartilage defects had been filled with a material similar to the surrounding
healthy cartilage.
Conclusion: HD-ACI is a safe and effective technique for focal cartilage lesion treatment in patients
affected by evolved FAI.

Referencia:

Torres-Eguia R, Lopez-Alcorocho JM, Rodriguez-Iñigo E, Guillen-Vicente I, Guillen-Vicente M, Diaz-Navarro ME, Aboli L, Fernández-Jaén TF, Guillen-Garcia P. The use of high-density autologous chondrocytes implant for the treatment of hip joint chondral defects. Journal of Cartilage & Joint preservation 2022

Link: https://doi.org/10.1016/j.jcjp.2022.100070