title: Mesenchymal Stem Cell Secretome: A Potential Tool for the Prevention of Muscle Degenerative Changes Associated With Chronic Rotator Cuff Tears.
abstract: Massive rotator cuff tears (MRCTs) are usually chronic lesions with pronounced degenerative changes, where advanced fatty degeneration and atrophy can make the tear irreparable. Human mesenchymal stem cells (hMSCs) secrete a range of growth factors and vesicular systems, known as secretome, that mediates regenerative processes in tissues undergoing degeneration.
  
  
  
  To study the effect of hMSC secretome on muscular degenerative changes and shoulder function on a rat MRCT model.
  
  
  
  Controlled laboratory study.
  
  
  
  A bilateral 2-tendon (supraspinatus and infraspinatus) section was performed to create an MRCT in a rat model. Forty-four Wistar-Han rats were randomly assigned to 6 groups: control group (sham surgery), lesion control group (MRCT), and 4 treated-lesion groups according to the site and periodicity of hMSC secretome injection: single local injection, multiple local injections, single systemic injection, and multiple systemic injections. Forelimb function was analyzed with the staircase test. Atrophy and fatty degeneration of the muscle were evaluated at 8 and 16 weeks after injury. A proteomic analysis was conducted to identify the molecules present in the hMSC secretome that can be associated with muscular degeneration prevention.
  
  
  
  When untreated for 8 weeks, the MRCT rats exhibited a significantly higher fat content (0.73% ± 0.19%) compared with rats treated with a single local injection (0.21% ± 0.04%; P < .01) or multiple systemic injections (0.25% ± 0.10%; P < .05) of hMSC secretome. At 16 weeks after injury, a protective effect of the secretome in the multiple systemic injections (0.62% ± 0.14%; P < .001), single local injection (0.76% ± 0.17%; P < .001), and multiple local injections (1.35% ± 0.21%; P < .05) was observed when compared with the untreated MRCT group (2.51% ± 0.42%). Regarding muscle atrophy, 8 weeks after injury, only the single local injection group (0.0993% ± 0.0036%) presented a significantly higher muscle mass than that of the untreated MRCT group (0.0794% ± 0.0047%; P < .05). Finally, the proteomic analysis revealed the presence of important proteins with muscle regeneration, namely, pigment epithelium-derived factor and follistatin.
  
  
  
  The study data suggest that hMSC secretome effectively decreases the fatty degeneration and atrophy of the rotator cuff muscles.
  
  
  
  We describe a new approach for decreasing the characteristic muscle degeneration associated with chronic rotator cuff tears. This strategy is particularly important for patients whose tendon healing after later surgical repair could be compromised by the progressing degenerative changes. In addition, both precise intramuscular local injection and multiple systemic secretome injections have been shown to be promising delivery forms for preventing muscle degeneration.
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, Braga, Portugal ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal Orthopaedics Department, Hospital de Braga, Braga, Portugal Clínica do Dragão, Espregueira-Mendes Sports Centre, FIFA Medical Centre of Excellence, Estádio do Dragão, Porto, Portugal.
authors: Nuno
authors: N
authors: Sevivas
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, Braga, Portugal ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Fábio Gabriel
authors: FG
authors: Teixeira
authors: Pathology Department, Centro Hospitalar São João, Porto, Portugal.
authors: Raquel
authors: R
authors: Portugal
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, Braga, Portugal ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Luís
authors: L
authors: Araújo
authors: Orthopaedics Department, Hospital de Braga, Braga, Portugal.
authors: Luís Filipe
authors: LF
authors: Carriço
authors: Orthopaedics Department, Hospital de Braga, Braga, Portugal Clínica do Dragão, Espregueira-Mendes Sports Centre, FIFA Medical Centre of Excellence, Estádio do Dragão, Porto, Portugal.
authors: Nuno
authors: N
authors: Ferreira
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, Braga, Portugal ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal Orthopaedics Department, Hospital de Braga, Braga, Portugal.
authors: Manuel
authors: M
authors: Vieira da Silva
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, Braga, Portugal ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal Clínica do Dragão, Espregueira-Mendes Sports Centre, FIFA Medical Centre of Excellence, Estádio do Dragão, Porto, Portugal 3B's Research Group, Biomaterials, Biodegradables and Biomimetics, Department of Polymer Engineering, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimarães, Portugal.
authors: João
authors: J
authors: Espregueira-Mendes
authors: Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal Faculty of Sciences and Technology, University of Coimbra, Coimbra, Portugal.
authors: Sandra
authors: S
authors: Anjo
authors: Center for Neuroscience and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal Biocant-Biotechnology Innovation Center, Cantanhede, Portugal.
authors: Bruno
authors: B
authors: Manadas
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, Braga, Portugal ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors: Nuno
authors: N
authors: Sousa
authors: Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Campus de Gualtar, Braga, Portugal ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal asalgado@ecsaude.uminho.pt.
authors: António J
authors: AJ
authors: Salgado
keywords: fatty degeneration; hMSC secretome; massive rotator cuff tear; muscle atrophy