Enhancement of msc immunomodulatory properties by treprostinil

Abstract

Provided are methods for treating or preventing vasculopathy comprising administering to a subject in need thereof, ac composition comprising a mesenchymal stem cell (MSC), or a part of a culture medium that has been in contact with the MSC and comprises one or more components of the MSC, or an exosome derived from the MSC. Pharmaceutical compositions suitable for such treatment is also provided.

1 . A method for preparing a composition comprising a mesenchymal stem cell (MSC) or a culture medium that has been in contact with the MSC and comprises one or more components of the MSC, comprising exposing the MSC to a prostacyclin ex vivo, and wherein the exposure with the prostacyclin increases the expression of one or more anti-inflammatory factors and/or reduces the expression of one or more pro-inflammatory factors in the MSC, compared to a control MSC not exposed to the prostacyclin; and
 isolating the MSC or at least a portion of the culture medium comprising exosomes.   
     
     
         2 . The method of  claim 1 , comprising exposing the MSC to 0.3 μg/mL to 50 μg/mL of prostacyclin. 
     
     
         3 . The method of  claim 1 , comprising exposing the MSC to 0.3 μg/mL to 10 μg/mL of prostacyclin. 
     
     
         4 . The method of  claim 1 , wherein the prostacyclin is treprostinil, a derivative or a salt thereof. 
     
     
         5 . The method of  claim 1 , wherein the MSC is exposed to the prostacyclin for at least 24 hours. 
     
     
         6 . The method of  claim 1 , wherein the MSC is exposed to the prostacyclin for at least 48 hours. 
     
     
         7 . The method of  claim 1 , wherein the MSC is exposed to the prostacyclin post-expansion. 
     
     
         8 . The method of  claim 1 , wherein the MSC exposed to the prostacyclin has a reduced expression level of TNFα, compared to a control MSC not exposed to the prostacyclin. 
     
     
         9 . The method of  claim 1 , wherein the MSC exposed to the prostacyclin has an increased expression level of one or more anti-inflammatory factors selected from the group consisting of IL10, IL13, IDO, iNOS, HLA and TGFβ, compared to a control MSC not exposed to the prostacyclin. 
     
     
         10 . The method of  claim 1 , wherein the MSC exposed to the prostacyclin has an expression level of TNFα that is at least 50% lower than that of a control MSC not exposed to the prostacyclin. 
     
     
         11 . The method of  claim 1 , wherein the MSC exposed to the prostacyclin has an expression level at least one of IL10, IL13, IDO, iNOS, HLA and TGFβ that is at least 50% higher than that of a control MSC not exposed to the prostacyclin. 
     
     
         12 . The method of  claim 1 , wherein the one or more components of the MSC is selected from the group consisting of an exosome, a microvesicle, a microRNA, a messenger RNA, a non-coding RNA, a mitochondria, a growth factor, and the combinations thereof. 
     
     
         13 . The method of  claim 1 , wherein the MSC is exposed to a composition comprising treprostinil or a salt thereof having a concentration of 0.3 μg/mL to 10 μg/mL for at least 24 hours. 
     
     
         14 . The method of  claim 1 , further comprising isolating an exosome from the culture medium. 
     
     
         15 . A composition comprising the isolated MSC obtained by the method of  claim 1 . 
     
     
         16 . A composition comprising the isolated exosome obtained by the method of  claim 1 . 
     
     
         17 . The composition of  claim 15 , further comprising at least one pharmaceutically acceptable carrier. 
     
     
         18 . The composition of  claim 15 , further comprising at least one additional therapeutic agent for treating or preventing vasculopathy. 
     
     
         19 . The composition of  claim 16 , further comprising at least one pharmaceutically acceptable carrier. 
     
     
         20 . The composition of  claim 16 , further comprising at least one additional therapeutic agent for treating or preventing vasculopathy. 
     
     
         21 . A composition comprising a population of MSCs having an altered gene expression pattern, wherein the altered gene expression pattern comprises an expression level of TNFα that is at least 50% lower than that of a control MSC and/or an expression level of at least one of IL10, IL13, IDO, iNOS, HLA and TGFβ that is at least 50% higher than that of a control MSC, wherein the population of MSCs having said altered gene expression pattern accounts for at least 50% of all MSCs in the composition.