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Journal ArticleDOI

Mesenchymal stem cells secretome: a new paradigm for central nervous system regeneration?

01 Mar 2013-Cellular and Molecular Life Sciences (Springer Basel)-Vol. 70, Iss: 20, pp 3871-3882
TL;DR: Considering their protective action in lesioned sites, MSCs’ secretome might also improve the integration of local progenitor cells in neuroregeneration processes, opening a door for their future use as therapeutic strategies in human clinical trials.
Abstract: The low regeneration potential of the central nervous system (CNS) represents a challenge for the development of new therapeutic strategies. Mesenchymal stem cells (MSCs) have been proposed as a possible therapeutic tool for CNS disorders. In addition to their differentiation potential, it is well accepted nowadays that their beneficial actions can also be mediated by their secretome. Indeed, it was already demonstrated, both in vitro and in vivo, that MSCs are able to secrete a broad range of neuroregulatory factors that promote an increase in neurogenesis, inhibition of apoptosis and glial scar formation, immunomodulation, angiogenesis, neuronal and glial cell survival, as well as relevant neuroprotective actions on different pathophysiological contexts. Considering their protective action in lesioned sites, MSCs’ secretome might also improve the integration of local progenitor cells in neuroregeneration processes, opening a door for their future use as therapeutical strategies in human clinical trials. Thus, in this review we analyze the current understanding of MSCs secretome as a new paradigm for the treatment of CNS neurodegenerative diseases.

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        
    
     
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 
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
         

        


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
        


       

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

  
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 
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      

      

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   
        
       

      

 

         





      

      


    

 



 











         
     
    






     
     
      

  
       
  





     

          


         
         
        








       
       
       

        
      



  








        









      
      


     
  
         







         
       

         
 





        

        


 
        

     


  






         
     
    


    
        
      


     
 



          
 

      
        
      

        
       


      

       

        



        

        






 
     

  
 

     


      
       
      


    
     
      
        
        
        




        

       






         
     
    


    
     




 
       



      

       
      
         
      
    


       
     
       


     



     
      



        

       




        


 
  

 
    





   

       
         
 

     









      



     
     


     


     

       


      

       





         
     
    




        

       
       
       

         


 
          

      
        
 
        
         

        
      
         
       

        


  



      





      
      

   

       
        



 
       






 




         
         
  

        
         
  
    




Citations
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Journal ArticleDOI
TL;DR: MSC-derived extracellular vesicles may be used as an alternative MSC-based therapy in regenerative medicine and their therapeutic potential in various diseases is discussed.
Abstract: Mesenchymal stem cells (MSCs) are multipotent stem cells that have gained significant attention in the field of regenerative medicine. The differentiation potential along with paracrine properties of MSCs have made them a key option for tissue repair. The paracrine functions of MSCs are applied through secreting soluble factors and releasing extracellular vesicles like exosomes and microvesicles. Extracellular vesicles are predominantly endosomal in origin and contain a cargo of miRNA, mRNA, and proteins that are transferred from their original cells to target cells. Recently it has emerged that extracellular vesicles alone are responsible for the therapeutic effect of MSCs in plenty of animal diseases models. Hence, MSC-derived extracellular vesicles may be used as an alternative MSC-based therapy in regenerative medicine. In this review we discuss MSC-derived extracellular vesicles and their therapeutic potential in various diseases.

390 citations


Cites background from "Mesenchymal stem cells secretome: a..."

  • ...In recent years, however, focus on the therapeutic effects of MSCs in regenerative medicine has been shifting to their activity through paracrine secretion instead of engraftment and differentiation into functional cells [2, 4]....

    [...]

  • ...MSCs are described as multipotent nonhematopoietic adult stem cells that express the surface markers CD90, CD105, and CD73, without the expression of CD14, CD34, and CD45 [4]....

    [...]

  • ...They were originally found by Friedenstein [4] via studies on the bone marrow in the 1960s but can be isolated from other adult tissues, such as adipose tissue, dental pulp, placenta, amniotic fluid, umbilical cord blood, Wharton’s jelly, and even the brain, spleen, liver, kidney, lung, thymus, and pancreas [4, 5]....

    [...]

Journal ArticleDOI
TL;DR: Recent reports of MSC aggregate self-assembly, characterization of biological properties, and their applications in preclinical models are summarized to provide perspectives for identifying the controlling mechanisms and refining the methods of aggregate fabrication and expansion for clinical applications.
Abstract: Mesenchymal stem cells (MSCs) are primary candidates in cell therapy and tissue engineering and are being tested in clinical trials for a wide range of diseases. Originally isolated and expanded as plastic adherent cells, MSCs have intriguing properties of in vitro self-assembly into three-dimensional (3D) aggregates reminiscent of skeletal condensation in vivo. Recent studies have shown that MSC 3D aggregation improved a range of biological properties, including multilineage potential, secretion of therapeutic factors, and resistance against ischemic condition. Hence, the formation of 3D MSC aggregates has been explored as a novel strategy to improve cell delivery, functional activation, and in vivo retention to enhance therapeutic outcomes. This article summarizes recent reports of MSC aggregate self-assembly, characterization of biological properties, and their applications in preclinical models. The cellular and molecular mechanisms underlying MSC aggregate formation and functional activation are discussed, and the areas that warrant further investigation are highlighted. These analyses are combined to provide perspectives for identifying the controlling mechanisms and refining the methods of aggregate fabrication and expansion for clinical applications.

322 citations

Journal ArticleDOI
TL;DR: The stem cell secretome (SCS) includes cytokines, chemokines and growth factors, and has gained increasing attention in recent years because of its multiple implications for the repair, restoration or regeneration of injured tissues.

285 citations

Journal ArticleDOI
TL;DR: More in depth studies that use uniform and standardized means of protein detection and analysis are necessary in light of the lack of uniformity in prior secretome-analysis studies, and the growing clinical importance of the ASC secretome.

262 citations

Journal ArticleDOI
TL;DR: Although MSCs have a potential to exert anti-tumor activities, they largely provide service to the tumor using the multidirectional communication system established by exosomes in the TME.

206 citations

References
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Journal ArticleDOI
TL;DR: The Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposes minimal criteria to define human MSC, believing this minimal set of standard criteria will foster a more uniform characterization of MSC and facilitate the exchange of data among investigators.

14,724 citations


"Mesenchymal stem cells secretome: a..." refers methods in this paper

  • ...According to the definition introduced by the International Society for Cellular Therapy (ISCT), there are some minimal criteria for the identification of MSCs populations, such as the adherence to plastic in standard culture conditions; positive expression of specific markers like CD73, CD90, CD105, and negative expression of hematopoietic markers like CD34, CD45, HLA-DR, CD14, or CD11B, CD79α or CD19; and in vitro differentiation into at least osteoblasts, adipocytes, and chondroblasts [11]....

    [...]

Journal ArticleDOI
TL;DR: It is shown that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location, and it is proposed that this RNA is called “exosomal shuttle RNA” (esRNA).
Abstract: Exosomes are vesicles of endocytic origin released by many cells. These vesicles can mediate communication between cells, facilitating processes such as antigen presentation. Here, we show that exosomes from a mouse and a human mast cell line (MC/9 and HMC-1, respectively), as well as primary bone marrow-derived mouse mast cells, contain RNA. Microarray assessments revealed the presence of mRNA from approximately 1300 genes, many of which are not present in the cytoplasm of the donor cell. In vitro translation proved that the exosome mRNAs were functional. Quality control RNA analysis of total RNA derived from exosomes also revealed presence of small RNAs, including microRNAs. The RNA from mast cell exosomes is transferable to other mouse and human mast cells. After transfer of mouse exosomal RNA to human mast cells, new mouse proteins were found in the recipient cells, indicating that transferred exosomal mRNA can be translated after entering another cell. In summary, we show that exosomes contain both mRNA and microRNA, which can be delivered to another cell, and can be functional in this new location. We propose that this RNA is called "exosomal shuttle RNA" (esRNA).

10,484 citations

Journal ArticleDOI
TL;DR: The data support the hypothesis that a human lipoaspirate contains multipotent cells and may represent an alternative stem cell source to bone marrow-derived MSCs.
Abstract: Future cell-based therapies such as tissue engineering will benefit from a source of autologous pluripotent stem cells. For mesodermal tissue engineering, one such source of cells is the bone marrow stroma. The bone marrow compartment contains several cell populations, including mesenchymal stem cells (MSCs) that are capable of differentiating into adipogenic, osteogenic, chondrogenic, and myogenic cells. However, autologous bone marrow procurement has potential limitations. An alternate source of autologous adult stem cells that is obtainable in large quantities, under local anesthesia, with minimal discomfort would be advantageous. In this study, we determined if a population of stem cells could be isolated from human adipose tissue. Human adipose tissue, obtained by suction-assisted lipectomy (i.e., liposuction), was processed to obtain a fibroblast-like population of cells or a processed lipoaspirate (PLA). These PLA cells can be maintained in vitro for extended periods with stable population doubling and low levels of senescence. Immunofluorescence and flow cytometry show that the majority of PLA cells are of mesodermal or mesenchymal origin with low levels of contaminating pericytes, endothelial cells, and smooth muscle cells. Finally, PLA cells differentiate in vitro into adipogenic, chondrogenic, myogenic, and osteogenic cells in the presence of lineage-specific induction factors. In conclusion, the data support the hypothesis that a human lipoaspirate contains multipotent cells and may represent an alternative stem cell source to bone marrow-derived MSCs.

7,402 citations


"Mesenchymal stem cells secretome: a..." refers background in this paper

  • ...Following these early studies, several reports have confirmed that MSCs are not only present within the bone marrow but also in other tissues like adipose tissue [13, 14], dental pulp [15, 16], placenta [17, 18], umbilical cord blood [19], Wharton’s jelly [20, 21], and brain [22]....

    [...]

Journal ArticleDOI
TL;DR: To confirm whether adipose tissue contains stem cells, the PLA population and multiple clonal isolates were analyzed using several molecular and biochemical approaches and PLA cells exhibited unique characteristics distinct from those seen in MSCs, including differences in CD marker profile and gene expression.
Abstract: Much of the work conducted on adult stem cells has focused on mesenchymal stem cells (MSCs) found within the bone marrow stroma. Adipose tissue, like bone marrow, is derived from the embryonic mesenchyme and contains a stroma that is easily isolated. Preliminary studies have recently identified a putative stem cell population within the adipose stromal compartment. This cell population, termed processed lipoaspirate (PLA) cells, can be isolated from human lipoaspirates and, like MSCs, differentiate toward the osteogenic, adipogenic, myogenic, and chondrogenic lineages. To confirm whether adipose tissue contains stem cells, the PLA population and multiple clonal isolates were analyzed using several molecular and biochemical approaches. PLA cells expressed multiple CD marker antigens similar to those observed on MSCs. Mesodermal lineage induction of PLA cells and clones resulted in the expression of multiple lineage-specific genes and proteins. Furthermore, biochemical analysis also confirmed lineage-specific activity. In addition to mesodermal capacity, PLA cells and clones differentiated into putative neurogenic cells, exhibiting a neuronal-like morphology and expressing several proteins consistent with the neuronal phenotype. Finally, PLA cells exhibited unique characteristics distinct from those seen in MSCs, including differences in CD marker profile and gene expression.

6,473 citations


"Mesenchymal stem cells secretome: a..." refers background in this paper

  • ...Following these early studies, several reports have confirmed that MSCs are not only present within the bone marrow but also in other tissues like adipose tissue [13, 14], dental pulp [15, 16], placenta [17, 18], umbilical cord blood [19], Wharton’s jelly [20, 21], and brain [22]....

    [...]

Journal ArticleDOI
TL;DR: Postnatal human DPSCs are isolated that have the ability to form a dentin/pulp-like complex and are compared with human bone marrow stromal cells, known precursors of osteoblasts.
Abstract: Dentinal repair in the postnatal organism occurs through the activity of specialized cells, odontoblasts, that are thought to be maintained by an as yet undefined precursor population associated with pulp tissue. In this study, we isolated a clonogenic, rapidly proliferative population of cells from adult human dental pulp. These DPSCs were then compared with human bone marrow stromal cells (BMSCs), known precursors of osteoblasts. Although they share a similar immunophenotype in vitro, functional studies showed that DPSCs produced only sporadic, but densely calcified nodules, and did not form adipocytes, whereas BMSCs routinely calcified throughout the adherent cell layer with clusters of lipid-laden adipocytes. When DPSCs were transplanted into immunocompromised mice, they generated a dentin-like structure lined with human odontoblast-like cells that surrounded a pulp-like interstitial tissue. In contrast, BMSCs formed lamellar bone containing osteocytes and surface-lining osteoblasts, surrounding a fibrous vascular tissue with active hematopoiesis and adipocytes. This study isolates postnatal human DPSCs that have the ability to form a dentin/pulp-like complex.

4,174 citations


"Mesenchymal stem cells secretome: a..." refers background in this paper

  • ...Following these early studies, several reports have confirmed that MSCs are not only present within the bone marrow but also in other tissues like adipose tissue [13, 14], dental pulp [15, 16], placenta [17, 18], umbilical cord blood [19], Wharton’s jelly [20, 21], and brain [22]....

    [...]

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