Lung Fibrosis Is Improved by Extracellular Vesicles from IFNγ-Primed Mesenchymal Stromal Cells in Murine Systemic Sclerosis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Mesenchymal Stromal Cell Expansion
2.2. Production and Isolation of EVs
2.3. Animal Model and Histopathological Analysis
2.4. RNA Extraction and RT-qPCR
2.4.1. Measure of Advanced Oxidation Protein Products
2.4.2. Measure of Anti-Oxidant Capacity
2.5. ELISA
2.6. Analysis of miRNA Profiles
2.7. Gene Ontology Pathway Analysis
2.8. Statistical Analysis
3. Results
3.1. A High Dose of MSC-EVs Was Not Beneficial to SSc Mice
3.2. Low Dose IFNγ Pre-Activation Improved the Anti-Fibrotic Effect of MSC-EVs in Lungs
3.3. High Dose IFNγ Pre-Activation Improved Remodeling and Anti-Inflammatory Effect of MSC-EVs in Lungs
3.4. IFNγ Pre-Activation Up-Regulated Anti-Inflammatory Factors in MSCs and MSC-EVs
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene Name | Sequence Forward | Sequence Reverse |
---|---|---|
Acta2(αSma) | AAGGCCAACCGGGAGAAAAT | AGCCAAGTCCAGACGCATGA |
Col1a1 | TGTTCAGCTTTGTGGACCTC | TCAAGCATACCTCGGGTTTC |
Col3a1 | CGGTGAACGGGGCGAAGCTGGTT | GACCCCTTTCTCCTGCGGCTCCT |
Cox2 | GCATTCTTTGCCCAGCACTT | AGACCAGGCACCAGACCAAAGA |
Gapdh | GGTGCTGAGTATGTCGTGGA | GTGGTTCACACCCATCACAA |
Hgf | TGCCCTATTTCCCGTTGTGA | CGCTTCTCCTCGCCTCTCTC |
Hmox1 | GCAGAGCCGTCTCGAGCATA | GCATTCTCGGCTTGGATGTG |
Il1ra | AGGCCCCACCACCAGCTTTGA | GGGGCTCTTCCGGTGTGTTGGT |
Il1β | TTTGACAGTGATGAGAATGACCTGTTC | TCATCAGGACAGCCCAGGTCAAAG |
Il6 | TGGGACTGATGCTGGTGACA | TTCCACGATTTCCCAGAGAACA |
iNos | CCTTGTTCAGCTACGCCTTC | GCTTGTCACCACCAGCAGTA |
Mmp1 | TTCAAAGGCAGCAAAGTATGGGCT | CCAGTCTCTTCTTCACAAACAGCAGCA |
Mmp9 | TCCAGTTTGGTGTCGCGGAGCACG | CAGGGGGAAAGGCGTGTGCCAGA |
Nfe2l2 | CGCCAGCTACTCCCAGGTTG | ACTTTCAGCGTGGCTGGGGA |
Sod2 | TCAGGACCCATTGCAAGGAA | TGTGGCCGTGAGTGACGTTT |
Tbp | GGGAGAATCATGGACCAGAA | CCGTAAGGCATCATTGGACT |
Tgfβ1 | TGCGCTTGCAGAGATTAAAA | CTGCCGTACAACTCCAGTGA |
TgfβR2 | CGACCCCAAGCTCACCTACC | CAACAACAGGTCGGGACTGC |
Timp1 | CTCCGCCCTTCGCATGGACATT | GGGGGCCATCATGGTATCTGCTCT |
Tnfα | AGCCCACGTCGTAGCAAACCA | TGTCTTTGAGATCCATGCCGTTGGC |
MSC | ssEV | lsEV | ||||
---|---|---|---|---|---|---|
−IFNγ | +IFNγ | −IFNγ | +IFNγ | −IFNγ | + IFNγ | |
let-7a-5p | 39,871 | 33,617 | 10,128 | 5963 | 21,047 | 21,213 |
let-7b-5p | 47,447 | 35,255 | 8648 | 4556 | 21,621 | 21,476 |
let-7c-3p | 403 | 0 | 0 | 0 | 0 | 0 |
let-7c-5p | 57,948 | 42,747 | 11,281 | 6154 | 26,131 | 26,347 |
let-7d-3p | 1097 | 879 | 1585 | 1000 | 1544 | 1455 |
let-7d-5p | 17,079 | 16,250 | 5002 | 3356 | 9475 | 8869 |
let-7e-3p | 253 | 0 | 0 | 0 | 0 | 0 |
let-7e-5p | 7938 | 6261 | 1621 | 1023 | 4224 | 4091 |
let-7f-1-3p | 245 | 114 | 0 | 0 | 0 | 0 |
let-7f-5p | 21,504 | 21,024 | 8136 | 4975 | 15,443 | 15,217 |
let-7g-5p | 6287 | 7170 | 3143 | 2408 | 4563 | 4024 |
let-7i-5p | 33,329 | 30,098 | 8184 | 4723 | 16,303 | 13,232 |
miR-100-5p | 7165 | 7546 | 2619 | 1675 | 5070 | 4458 |
miR-101-3p | 513 | 1572 | 1757 | 2085 | 1188 | 1221 |
miR-103a-2-5p | 367 | 168 | 0 | 0 | 0 | 0 |
miR-103a-3p | 2655 | 2334 | 1695 | 1429 | 1978 | 1613 |
miR-106b-3p | 521 | 275 | 0 | 631 | 0 | 0 |
miR-106b-5p | 1881 | 2134 | 3213 | 3287 | 2228 | 2239 |
miR-107 | 1667 | 1684 | 1127 | 1070 | 1170 | 0 |
miR-1247-5p | 2752 | 1116 | 0 | 598 | 1544 | 1207 |
miR-1249 | 1213 | 626 | 4544 | 4571 | 3003 | 2429 |
miR-125a-3p | 745 | 328 | 0 | 0 | 0 | 0 |
miR-125a-5p | 13,783 | 15,755 | 5304 | 3068 | 11,867 | 10,808 |
miR-125b-1-3p | 3316 | 944 | 0 | 0 | 0 | 0 |
miR-125b-5p | 55,996 | 50,774 | 15,833 | 8527 | 31,962 | 31,144 |
miR-126-3p | 0 | 0 | 4183 | 4440 | 1692 | 1555 |
miR-126-5p | 0 | 0 | 2105 | 2089 | 1070 | 0 |
miR-128-3p | 454 | 424 | 0 | 668 | 0 | 0 |
miR-130a-3p | 7587 | 9334 | 3461 | 1860 | 5813 | 5799 |
miR-130b-3p | 1339 | 2413 | 1193 | 821 | 2200 | 2280 |
miR-140-5p | 1309 | 1419 | 0 | 0 | 1333 | 0 |
miR-142-5p | 0 | 0 | 5341 | 5417 | 2163 | 1799 |
miR-143-3p | 27,877 | 31,702 | 14,591 | 8415 | 25,698 | 21,680 |
miR-144-3p | 0 | 0 | 12,449 | 18,149 | 3434 | 2808 |
miR-145-5p | 37,004 | 33,556 | 16,311 | 8731 | 36,226 | 35,290 |
miR-146b-5p | 4779 | 7806 | 1639 | 1519 | 3429 | 4867 |
miR-148a-3p | 2180 | 2622 | 1247 | 903 | 1602 | 2148 |
miR-148b-3p | 1009 | 974 | 0 | 728 | 0 | 0 |
miR-149-5p | 1796 | 720 | 0 | 0 | 1292 | 0 |
miR-150-5p | 0 | 0 | 3595 | 3486 | 1920 | 1511 |
miR-152-3p | 1854 | 2393 | 0 | 0 | 1209 | 1746 |
miR-15a-5p | 9268 | 11,252 | 8791 | 6577 | 10,976 | 7963 |
miR-15b-5p | 10,225 | 11,817 | 7676 | 4862 | 12,178 | 8735 |
miR-16-5p | 23,877 | 29,760 | 24,744 | 19,313 | 33,102 | 24,885 |
miR-17-5p | 3092 | 3465 | 3345 | 2828 | 3773 | 3677 |
miR-181a-3p | 270 | 0 | 0 | 0 | 0 | 0 |
miR-181a-5p | 2155 | 1557 | 1241 | 1021 | 1466 | 1414 |
miR-181b-5p | 944 | 634 | 0 | 0 | 0 | 0 |
miR-181d-5p | 714 | 473 | 0 | 0 | 0 | 0 |
miR-183-5p | 527 | 365 | 0 | 0 | 0 | 0 |
miR-185-5p | 610 | 540 | 0 | 632 | 0 | 0 |
miR-186-5p | 1164 | 1372 | 1963 | 1844 | 1696 | 1709 |
miR-18a-5p | 437 | 457 | 0 | 0 | 0 | 0 |
miR-191-5p | 3574 | 3677 | 3092 | 2965 | 3710 | 4040 |
miR-193a-3p | 3563 | 2401 | 0 | 587 | 2061 | 2227 |
miR-195-5p | 374 | 804 | 0 | 0 | 1055 | 0 |
miR-196a-5p | 5952 | 4730 | 1297 | 602 | 3301 | 3194 |
miR-196b-3p | 815 | 223 | 0 | 0 | 0 | 0 |
miR-196b-5p | 2520 | 2101 | 0 | 0 | 1290 | 0 |
miR-199a-5p | 15,996 | 17,854 | 6145 | 3584 | 13,123 | 13,706 |
miR-19a-3p | 1182 | 1504 | 2363 | 2298 | 2326 | 1862 |
miR-19b-3p | 6114 | 5510 | 6119 | 5431 | 6073 | 5334 |
miR-204-3p | 992 | 285 | 0 | 578 | 0 | 0 |
miR-205-5p | 0 | 117 | 0 | 0 | 1655 | 0 |
miR-20a-5p | 1715 | 2219 | 2308 | 1860 | 2061 | 2192 |
miR-20b-5p | 1504 | 1628 | 1924 | 1286 | 2043 | 1913 |
miR-210-3p | 7921 | 5347 | 1569 | 1288 | 3041 | 3329 |
miR-214-5p | 772 | 860 | 0 | 0 | 0 | 0 |
miR-21-5p | 56,378 | 115,717 | 50,802 | 29,227 | 84,586 | 76,286 |
miR-218-5p | 1364 | 3301 | 0 | 0 | 942 | 1318 |
miR-221-3p | 60,280 | 36,507 | 17,469 | 9313 | 37,071 | 32,350 |
miR-222-3p | 45,874 | 33,045 | 13,637 | 6941 | 31,186 | 26,064 |
miR-223-3p | 0 | 0 | 10,435 | 11,464 | 3899 | 3621 |
miR-22-3p | 30,464 | 35,897 | 9711 | 5829 | 19,711 | 16,146 |
miR-22-5p | 831 | 857 | 0 | 0 | 0 | 0 |
miR-23a-3p | 14,530 | 15,288 | 9451 | 6039 | 17,685 | 18,471 |
miR-23a-5p | 1364 | 318 | 0 | 0 | 1541 | 1513 |
miR-23b-3p | 9879 | 11,605 | 7103 | 4374 | 12,388 | 13,316 |
miR-24-3p | 14,019 | 13,811 | 5365 | 3360 | 10,476 | 10,575 |
miR-25-3p | 3410 | 3478 | 4018 | 4686 | 3312 | 3240 |
miR-26a-5p | 14,943 | 24,472 | 11,473 | 8941 | 16,360 | 14,933 |
miR-26b-5p | 4340 | 5251 | 5304 | 4160 | 5172 | 4732 |
miR-27a-3p | 9509 | 9645 | 11,580 | 5186 | 18,358 | 13,643 |
miR-27a-5p | 542 | 183 | 0 | 0 | 0 | 0 |
miR-27b-3p | 3745 | 5331 | 5673 | 2863 | 10,455 | 7796 |
miR-28-5p | 2498 | 2798 | 0 | 0 | 1707 | 1785 |
miR-29a-3p | 32,286 | 36,765 | 14,087 | 7669 | 29,072 | 29,852 |
miR-29a-5p | 442 | 545 | 0 | 0 | 0 | 0 |
miR-29b-3p | 33,224 | 43,943 | 15,536 | 7714 | 27,775 | 26,096 |
miR-29c-3p | 1299 | 3281 | 1722 | 1594 | 3460 | 3008 |
miR-301a-3p | 1613 | 1329 | 1057 | 687 | 1350 | 1342 |
miR-30a-3p | 431 | 298 | 0 | 0 | 0 | 0 |
miR-30a-5p | 3415 | 4477 | 2124 | 1653 | 3523 | 3333 |
miR-30b-5p | 3544 | 4877 | 4024 | 3000 | 5261 | 4684 |
miR-30c-2-3p | 253 | 122 | 0 | 0 | 0 | 0 |
miR-30c-5p | 5151 | 7006 | 4198 | 2929 | 5608 | 4956 |
miR-30d-5p | 4961 | 5492 | 2658 | 1607 | 4626 | 4038 |
miR-30e-3p | 464 | 299 | 0 | 0 | 0 | 0 |
miR-30e-5p | 1188 | 1537 | 1222 | 953 | 1537 | 1351 |
miR-320a | 2177 | 1001 | 0 | 576 | 1707 | 1609 |
miR-324-5p | 970 | 620 | 0 | 0 | 0 | 0 |
miR-328-3p | 1955 | 975 | 0 | 1194 | 1092 | 1342 |
miR-331-3p | 829 | 642 | 0 | 0 | 0 | 0 |
miR-33a-5p | 2930 | 2128 | 0 | 625 | 1409 | 1453 |
miR-342-3p | 0 | 154 | 1680 | 1424 | 0 | 0 |
miR-34a-5p | 2393 | 2012 | 0 | 0 | 1242 | 1193 |
miR-34c-5p | 8039 | 7379 | 2217 | 1038 | 4598 | 3652 |
miR-361-5p | 304 | 478 | 0 | 0 | 0 | 0 |
miR-374b-5p | 685 | 749 | 0 | 0 | 1272 | 0 |
miR-425-5p | 1256 | 1249 | 1076 | 1122 | 966 | 0 |
miR-451a | 0 | 0 | 194,289 | 267,727 | 46,810 | 40,211 |
miR-484 | 6203 | 5410 | 2543 | 1564 | 4918 | 5300 |
miR-486-5p | 0 | 146 | 3971 | 5677 | 1179 | 0 |
miR-532-3p | 354 | 254 | 1239 | 2490 | 0 | 1400 |
miR-532-5p | 251 | 258 | 0 | 0 | 0 | 0 |
miR-574-3p | 5199 | 3713 | 48,691 | 74,742 | 25,101 | 48,180 |
miR-574-5p | 20,670 | 18,789 | 180,234 | 217,257 | 78,303 | 149,525 |
miR-615-3p | 1621 | 944 | 0 | 0 | 1150 | 0 |
miR-652-3p | 1455 | 1110 | 0 | 860 | 927 | 0 |
miR-671-5p | 431 | 149 | 0 | 0 | 0 | 0 |
miR-6766-3p | 3846 | 222 | 0 | 1818 | 0 | 0 |
miR-7-1-3p | 346 | 307 | 0 | 0 | 0 | 0 |
miR-744-5p | 254 | 141 | 0 | 0 | 0 | 0 |
miR-7-5p | 9101 | 10,666 | 3405 | 897 | 6088 | 3271 |
miR-877-5p | 284 | 0 | 0 | 0 | 0 | 0 |
miR-92b-3p | 1302 | 1503 | 0 | 866 | 1478 | 1527 |
miR-93-5p | 3329 | 3218 | 3205 | 2549 | 3023 | 3064 |
miR-96-5p | 1243 | 965 | 0 | 0 | 0 | 0 |
miR-99a-5p | 7734 | 8614 | 2852 | 1730 | 5380 | 5383 |
miR-99b-3p | 550 | 288 | 0 | 0 | 0 | 0 |
miR-99b-5p | 6388 | 5799 | 2252 | 1342 | 5311 | 4932 |
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Rozier, P.; Maumus, M.; Maria, A.T.J.; Toupet, K.; Jorgensen, C.; Guilpain, P.; Noël, D. Lung Fibrosis Is Improved by Extracellular Vesicles from IFNγ-Primed Mesenchymal Stromal Cells in Murine Systemic Sclerosis. Cells 2021, 10, 2727. https://doi.org/10.3390/cells10102727
Rozier P, Maumus M, Maria ATJ, Toupet K, Jorgensen C, Guilpain P, Noël D. Lung Fibrosis Is Improved by Extracellular Vesicles from IFNγ-Primed Mesenchymal Stromal Cells in Murine Systemic Sclerosis. Cells. 2021; 10(10):2727. https://doi.org/10.3390/cells10102727
Chicago/Turabian StyleRozier, Pauline, Marie Maumus, Alexandre Thibault Jacques Maria, Karine Toupet, Christian Jorgensen, Philippe Guilpain, and Danièle Noël. 2021. "Lung Fibrosis Is Improved by Extracellular Vesicles from IFNγ-Primed Mesenchymal Stromal Cells in Murine Systemic Sclerosis" Cells 10, no. 10: 2727. https://doi.org/10.3390/cells10102727