Rotator Cuff Tear Size Regulates Fibroadipogenic Progenitor Number and Gene Expression Profile in the Supraspinatus Independent of Patient Age

2021 ◽  
pp. 036354652110545
Author(s):  
Michael R. Davies ◽  
Hannah Chi ◽  
Gurbani Kaur ◽  
Mengyao Liu ◽  
C. Benjamin Ma ◽  
...  

Background: Fatty infiltration of rotator cuff muscle is a limiting factor in the success of repairs. Fibroadipogenic progenitors (FAPs) are a population of stem cells within the rotator cuff that can differentiate into white adipocytes, fibroblasts, and beige adipocytes. The effects of patient age and rotator cuff tendon tear size on the number, differentiation patterns, and gene expression profiles of FAPs have not yet been analyzed. Purpose: To determine if patient age and rotator cuff tear size independently regulate FAP number, differentiation patterns, and gene expression profiles. Study Design: Controlled laboratory study. Methods: Supraspinatus muscle samples were collected from 26 patients between the ages of 42 and 76 years with partial- or full-thickness rotator cuff tears. FAPs were quantified using fluorescence-activated cell sorting. Gene expression analysis was performed across a custom 96-gene panel using NanoString. In vitro differentiation assays of FAPs were conducted using adipogenic, fibrogenic, and beige-inducing (amibegron-treated) media, and quantitative polymerase chain reaction was used to assess gene expression differences between adipogenic and amibegron media conditions. Multivariable linear regressions were performed using Stata to independently analyze the effects of age and rotator cuff tear size on FAP number, differentiation, and gene expression. Results: Increasing age and tear size were independently correlated with increased FAP number (βage = 0.21, P = .03; βtear size = 3.86, P = .05). There was no clear association between age and gene expression of freshly sorted FAPs. Under adipogenic and fibrogenic media conditions, increasing age and tear size were independently associated with increased adipogenic and fibrogenic differentiation of FAPs. Under amibegron treatment conditions, age positively correlated with increased beige differentiation (β = 1.03; P < .0001), while increasing tear size showed a trend toward decreased beige differentiation (β = −4.87; P = .1). When gene expression patterns between adipogenic and amibegron media conditions were compared, larger tear size strongly inhibited beige gene expression, while advanced age did not. Conclusion: Patient age and rotator cuff tear size independently regulated FAP number, differentiation, and gene expression. Age and tear size were positively correlated with increased FAP number and fibrogenic/adipogenic differentiation. Advancing patient age did not limit FAP beige differentiation and gene expression, while increasing rotator cuff tear size strongly inhibited these processes.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 412-412
Author(s):  
Huining Kang ◽  
Carla S. Wilson ◽  
Richard C. Harvey ◽  
I-Ming Chen ◽  
Maurice H. Murphy ◽  
...  

Abstract Abstract 412 ALL arising in infants is a highly refractory disease. Overall event-free survival (EFS) remains poor and infants with MLL rearrangements (MLL-R) or those <90 days of age are known to have particularly poor outcomes. To identify genes predictive of event-free survival (EFS) that might serve as new diagnostic and therapeutic targets, we completed gene expression profiling (Affymetrix HG_U133Plus2) in 97 infant ALL cases registered to COG Clinical Trial P9407. Of these 97 infants, 78 were most recently uniformly treated on P9407 cohort 3. In the 97 cases, median age at diagnosis was 166 days (range 1–365) and increased age at diagnosis was significantly associated with improved EFS (P = 0.001). 89/97 infants had MLL-R, of which 49 had an AF4 partner gene (MLL-AF4 (AFF1)). Infants <90 days of age (P=.0001) and those with MLL-R (MLL-AF4, MLL-ENL (MLLT1), MLL-Other) had a significantly decreased EFS, while infants with MLL-AF9 (MLLT3) or cases lacking MLL-R had a significantly better EFS (P=0.014). From modeling expression profiles and multivariate analyses, a number of genes were identified that had a significant effect on EFS and were independent of patient age or MLL-R status, including: TACC2 and IRX2 (from modeling the entire cohort of 97 cases); RORA, IGJ, ZEB1, YES1 (cohort 3 modeled alone); and IRX1, IRX2, ST3GAL6, HLA-DQB1, STAB1, NEGR1, IRX5 (MLL-AF4 cases modeled alone). The significant effect of MEIS1 and KCNK12 expression on EFS was lost after consideration of MLL-R status, while the significance of many genes (particularly in the HOXA family) was not independent of patient age in multivariate analyses. Assessment of the expression levels of two genes alone at diagnosis: TACC2 and IRX2 in the entire cohort of 97 cases (P<0.0001; Fig. A), or, NEGRI and IRX2 in the MLL-AF4 cases (P<0.0001; Fig. B), were highly predictive of outcome on current treatment regimens. Distinctive and strikingly different gene expression profiles were also seen in infant ALL cases <90 days of age vs. >90 days of age (in the overall cohort and in the MLL-AF4 cases). Specifically evaluating the impact of patient age treated as a continuous variable revealed a striking transition in expression profiles at 90 days with a differential expression pattern involving many genes encoding histone-related, heat shock family, or immune response regulators (including HLA-DRB4, IL1R2, HSPA1A///1B). These distinctive profiles may reflect different transformed stem/precursor cells or susceptibilities to leukemic transformation at different patient ages, altered marrow microenvironments, or altered immune status; high expression of the heat shock proteins in particular among the youngest infants may reflect a more limited immune surveillance capacity. Given the rarity of infant ALL, this study represents one of the largest uniformly treated groups of infant leukemia to undergo gene expression profiling. In these studies we have identified genes that are highly predictive of outcome at diagnosis, in all infant ALL and in MLL-AF4 cases. Further analysis of these expression profiles, coupled with validation studies in other infant ALL cohorts, may allow for the identification of novel therapeutic targets among the genes discovered herein and ultimately for the development of more effective therapies. Disclosures: Felix: None: Patent not licensed.


2021 ◽  
Vol 49 (2) ◽  
pp. 332-339
Author(s):  
Hideyuki Shirasawa ◽  
Noboru Matsumura ◽  
Masaki Yoda ◽  
Kazumasa Okubo ◽  
Masayuki Shimoda ◽  
...  

Background: The infiltration of fat tissue into skeletal muscle, a condition referred to as muscle fatty infiltration or fatty degeneration, is regarded as an irreversible event that significantly compromises the motor function of skeletal muscle. Purpose: To investigate the effect of retinoic acid receptor (RAR) agonists in suppressing the adipogenic differentiation of fibroadipogenic progenitors (FAPs) in vitro and fatty infiltration after rotator cuff tear in mice. Study Design: Controlled laboratory study. Methods: FAPs isolated from mouse skeletal muscle were cultured in adipogenic differentiation medium in the presence or absence of an RAR agonist. At the end of cell culture, adipogenic differentiation was evaluated by gene expression analysis and oil red O staining. A mouse model of fatty infiltration—which includes the resection of the rotator cuff, removal of the humeral head, and denervation the supraspinatus muscle—was used to induce fatty infiltration in the supraspinatus muscle. The mice were orally or intramuscularly administered with an RAR agonist after the surgery. Muscle fatty infiltration was evaluated by histology and gene expression analysis. Results: RAR agonists effectively inhibited the adipogenic differentiation of FAPs in vitro. Oral and intramuscular administration of RAR agonists suppressed the development of muscle fatty infiltration in the mice after rotator cuff tear. In accordance, we found a significant decrease in the number of intramuscular fat cells and suppressed expression in adipogenic markers. RAR agonists also increased the expression of the transcripts for collagens; however, an accumulation of collagenous tissues was not histologically evident in the present model. Conclusion: Muscle fatty infiltration can be alleviated by RAR agonists through suppressing the adipogenic differentiation of FAPs. The results also suggest that RAR agonists are potential therapeutic agents for treating patients who are at risk of developing muscle fatty infiltration. The consequence of the increased expression of collagen transcripts by RAR agonists needs to be clarified. Clinical Relevance: RAR agonists can be used to prevent the development of muscle fatty infiltration after rotator cuff tear. Nevertheless, further studies are mandatory in a large animal model to examine the safety and efficacy of intramuscular injection of RAR agonists.


2020 ◽  
Vol 40 (4) ◽  
Author(s):  
Jin Li ◽  
Lifeng Jiang ◽  
Xindie Zhou ◽  
Lidong Wu ◽  
Dong Li ◽  
...  

Abstract Expression of proinflammatory cytokines, such as interleukin (IL)-6 (IL-6) and metalloproteases, are elevated in patients with rotator cuff tear (RCT). In order to investigate the role of IL-6 gene polymorphisms on RCT risk, we genotyped two SNPs on IL-6 gene (rs1800795 and rs1800797) in 138 RCT patients and 137 healthy controls using polymerase chain reaction (PCR) and Sanger sequencing. The IL-6 expression in shoulder joint synovial fluid was determined by using enzyme-linked immunosorbent assay (ELISA) method. The constant score and visual analog scale (VAS) were used to evaluate the clinical outcome of two s (surgicsal vs. conservative) for RCT patients. For rs1800795, individuals with the GG genotype or G allele had significantly higher risk of RCT. Elevated risk of tear size was associated with the GG genotype of the rs1800795 polymorphism. The IL-6 rs1800797 polymorphism was also associated with an increased risk of RCT, especially among female, drinkers, and individuals with B(MI) &lt; 25 kg/m2. The elevated levels of IL-6 gene were observed among the mutant genotype of rs1800795/rs1800797 polymorphism. Surgical group is significantly better than conservative treatment from the perspective of constant score and VAS. Furthermore, CG genotype of rs1800795 polymorphism increased the constant score at 6 months in comparison with CC genotype. In conclusion, our study supports a role of IL-6 rs1800795/rs1800797 polymorphisms on increased RCT risk. The RCT patients with CG genotype of rs1800795 polymorphism have more obvious surgical treatment effects by influencing the IL-6 expression.


2013 ◽  
Vol 22 (10) ◽  
pp. e31-e32
Author(s):  
Lauren H. Redler ◽  
Ian R. Byram ◽  
Timothy J. Luchetti ◽  
Ying Lai Tsui ◽  
Todd C. Moen ◽  
...  

2013 ◽  
Vol 97 (S1) ◽  
pp. 69-72 ◽  
Author(s):  
S. Gumina ◽  
S. Carbone ◽  
V. Campagna ◽  
V. Candela ◽  
F. M. Sacchetti ◽  
...  

2016 ◽  
pp. 69-70
Author(s):  
Stefano Gumina ◽  
Stefano Carbone

2013 ◽  
Vol 22 (6) ◽  
pp. e6-e10 ◽  
Author(s):  
Gabriel J. Rulewicz ◽  
Stacy Beaty ◽  
Richard J. Hawkins ◽  
Michael J. Kissenberth

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