Enhanced placental stem cells and uses thereof

Abstract

Provided herein are placental stem cells that exhibit increased survival (“enhanced placental stem cells”), compositions comprising such placental stem cells, and methods of using such placental stem cells and compositions.

1 . An isolated placental stem cell, wherein said placental stem cell demonstrates increased survival relative to corresponding unmodified placental stem cells when cultured under one or more conditions that cause cell death. 
     
     
         2 . An isolated placental stem cell, wherein said placental stem cell expresses at least one survival-associated gene at a decreased level as compared to the expression of the same survival-associated gene in a corresponding unmodified placental stem cell. 
     
     
         3 . The isolated placental stem cell of  claim 2 , wherein said survival-associated gene is ADAMTS9, ABCF2, DNAJB4, MYB, RTN4, ANLN, BACE1, ABHD10, EGFR, NAA15, SEC24A MAP2K1, BCL2, ACTR1A, EIF4E, NAA25, SHOC2, CCNF, CAV2, ACVR2A, EPT1, NAPG, SLC12A2, CDC14A, CD276, ADSS, FGF2, NOB1, SLC16A3, CDC25A, CDC42, ALG3, FNDC3B, NOTCH2, SLC25A22, CHEK1, CDK6, ARHGDIA, GALNT7, SLC38A5, CUL2, COL3A1, ARL2, GPAM, PDCD4, SLC7A1, FGFR1, COL4A1, ATG9A, HACE1, PDCD6IP, SNX15, ITPR1, COL4A2, PLAG1, HARS, PHKB, SPTLC1, KIF23, CPEB3, C9ORF167/TOR4A, HARS2, PISD, SQSTM1, TRIM63, CXXC6/TET1, C9ORF89, HERC6, PLK1, SRPR, CSHL1, DIABLO, CACNA2D1, HMGA1, PNN, SRPRB, WEE1, DNMT3A, CAPRINE HSDL2, PNPLA6, TMEM43, MLLT1, DNMT3B, CCDC109A/MCU, IGF2R, PPIF, TNFSF9, MMS19, FGA, CCND1, IPO4, SIAH1, TOMM34, RECK, IMPDH1, CCND3, ITGA2, PPP2R5C, TPM3, RNASEL, INSIG1, CCNE1, KCNN4, PSAT1, TPPP3, WT1, KREMEN2, CCNT2, KPNA3, PTCD3, UBE2V1, YIF1B, LPL, CDC14B, LAMC1, PTGS2, UBE4A, ZNF622, MCL1, CDK5RAP1, LAMTOR3, PURA, UGDH, PIK3R1, CENPJ, LUZP1, RAB9B, UTP15, PPM1D, CHORDC1, LYPLA2, RAD51C, VEGFA, SPARC, CREBL2, PIAS1, RARS, or WNT3A. 
     
     
         4 . The isolated placental stem cell of  claim 3 , wherein said survival-associated gene is CCND1, CCND3, CCNE1, CCNF, CDK6, PPP2R5C, CDC25A, WEE1, CHEK1, MCL1, BCL2, PPMID, HMGA1, AKT3, VEGFA, MYB, and/or ITGA2. 
     
     
         5 . The isolated placental stem cell of  claim 1 , wherein said placental stem cell exhibits (i) decreased expression of caspase 3/7, (ii) increased mitochondrial membrane potential, and/or (iii) increased metabolic activity when cultured under one or more conditions that cause cell death as compared to corresponding unmodified placental stem cells cultured under the same condition(s). 
     
     
         6 . An isolated population of cells, wherein at least 50% of the cells in said population are the cells of  claim 1 . 
     
     
         7 . The isolated population of cells of  claim 6 , wherein at least 60%, at least 70%, at least 75%, at least 80%, and least 85%, at least 90%, at least 95%, or at least 99% of the cells in said population of cells are enhanced placental stem cells. 
     
     
         8 . A method of producing placental stem cells that demonstrate increased survival relative to corresponding unmodified placental stem cells when cultured under one or more conditions that cause cell death, said method comprising contacting a population of placental stem cells with an effective amount of modulatory RNA molecules, such that said placental stem cells, after having been contacted with said modulatory RNA molecules express at least one survival-associated gene at a decreased level as compared to the expression of the same survival-associated gene in an equivalent amount of placental stem cells not contacted with said modulatory RNA molecules. 
     
     
         9 . The method of  claim 8 , wherein said modulatory RNA molecules comprise microRNA (miRNA), micro RNA mimics (miRNA mimics), small interfering RNAs (siRNAs), antisense RNAs, short hairpin RNAs (shRNAs), or any combinations thereof. 
     
     
         10 . The method of  claim 8 , wherein said modulatory RNA molecules target at least one survival-associated gene of said placental stem cells. 
     
     
         11 . The method of  claim 10 , wherein said survival-associated gene is ADAMTS9, ABCF2, DNAJB4, MYB, RTN4, ANLN, BACE1, ABHD10, EGFR, NAA15, SEC24A MAP2K1, BCL2, ACTR1A, EIF4E, NAA25, SHOC2, CCNF, CAV2, ACVR2A, EPT1, NAPG, SLC12A2, CDC14A, CD276, ADSS, FGF2, NOB1, SLC16A3, CDC25A, CDC42, ALG3, FNDC3B, NOTCH2, SLC25A22, CHEK1, CDK6, ARHGDIA, GALNT7, SLC38A5, CUL2, COL3A1, ARL2, GPAM, PDCD4, SLC7A1, FGFR1, COL4A1, ATG9A, HACE1, PDCD6IP, SNX15, ITPR1, COL4A2, PLAG1, HARS, PHKB, SPTLC1, KIF23, CPEB3, C9ORF167/TOR4A, HARS2, PISD, SQSTM1, TRIM63, CXXC6/TET1, C9ORF89, HERC6, PLK1, SRPR, CSHL1, DIABLO, CACNA2D1, HMGA1, PNN, SRPRB, WEE1, DNMT3A, CAPRIN1, HSDL2, PNPLA6, TMEM43, MLLT1, DNMT3B, CCDC109A/MCU, IGF2R, PPIF, TNFSF9, MMS19, FGA, CCND1, IPO4, SIAH1, TOMM34, RECK, IMPDH1, CCND3, ITGA2, PPP2R5C, TPM3, RNASEL, INSIG1, CCNE1, KCNN4, PSAT1, TPPP3, WT1, KREMEN2, CCNT2, KPNA3, PTCD3, UBE2V1, YIF1B, LPL, CDC14B, LAMC1, PTGS2, UBE4A, ZNF622, MCL1, CDK5RAP1, LAMTOR3, PURA, UGDH, PIK3R1, CENPJ, LUZP1, RAB9B, UTP15, PPM1D, CHORDC1, LYPLA2, RAD51C, VEGFA, SPARC, CREBL2, PIAS1, RARS, or WNT3A. 
     
     
         12 . The method of  claim 11 , wherein said survival-associated gene is CCND1, CCND3, CCNE1, CCNF, CDK6, PPP2R5C, CDC25A, WEE1, CHEK1, MCL1, BCL2, PPMID, HMGA1, AKT3, VEGFA, MYB, and/or ITGA2. 
     
     
         13 . An isolated enhanced placental stem cell or population thereof produced by the method of  claim 8 . 
     
     
         14 . A composition comprising the isolated enhanced placental stem cell of  claim 1 . 
     
     
         15 . A composition comprising an isolated enhanced placental stem cell produced by the method of  claim 8 . 
     
     
         16 . The placental stem cell of  claim 1 , wherein said placental stem cell is a CD10 + , CD34 − , CD105 + , CD200 +  placental stem cell. 
     
     
         17 . The population of cells of  claim 6 , wherein said enhanced placental stem cells in said population are CD10 + , CD34 − , CD105 + , CD200 +  placental stem cells. 
     
     
         18 . The method of  claim 8 , wherein said enhanced placental stem cells are CD10 + , CD34 − , CD105 + , CD200 +  placental stem cells. 
     
     
         19 . The composition of  claim 14 , wherein said enhanced placental stem cells are CD10 + , CD34 − , CD105 + , CD200 +  placental stem cells.