Long Term Response to Circulating Angiogenic Cells, Unstimulated or Atherosclerotic Pre-Conditioned, in Critical Limb Ischemic Mice
Abstract
:1. Introduction
2. Materials and Methods
2.1. Cell Isolation and Culture
2.2. AP Secretome Acquisition
2.3. Murine Model of CLI. CACs Administration
2.4. Follow-Up of Physiological Changes after CLI and Cell Administration
2.5. Tissue Extraction
2.6. Immunohistochemical Analysis
2.7. Alu-Based Quantification
2.8. Proteomic Analysis
2.9. Cytokine Expression Analysis
2.10. Statistical Analysis
3. Results
3.1. CACs Promote Blood Flow Recovery in CLI Mice
3.2. CACs Delays Ischemic Progression in CLI Mice
3.3. Vascular Density Stabilizes at Day 21
3.4. Human CACs Are Not Present in Ischemic Tissues after 21 Days Post-Transplantation
3.5. Proteomic Changes Related to Long-Term CLI and CACs Treatment
3.5.1. Long-Term Protein Changes Due to Ischemia
3.5.2. CACs Long Term Effect at the Molecular Level
3.5.3. CACs Atherosclerotic Pre-Conditioning Effect
3.6. CACs Treatment Decrease Recruitment of Immune Cells
4. Discussion
4.1. Long Term Protein Changes Related to Ischemia
4.2. Molecular Changes in Response to CACs
4.3. CACs Pre-Stimulation with Atherosclerotic Plaque Secretomes
4.4. Modulation of Immune Cell Recruitment by CACs
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Categories | Functions (p-Value) | Activation z-Score | Molecules | Proteins |
---|---|---|---|---|
Cardiovascular System Development and Function | Vasculature development (1.29E-06) | 2.856 ▲ | ABI1↑, ADD1↑, ANXA1↑, APOE↑, CASP3↑, CD34↑, COL4A1↑, COMMD1↑, CYBA↑, CYBB↑, EMILIN1↑, F11R↑, FLNA↑, G6PD↑, GIT1↑, GLUL↑, HLA-DQB1↑, HSPB1↑, HSPB6↑, HSPB7↑, HSPG2↑, IGFBP7↑, LAMA4↑, LGALS3↑, LRP1↑, Mcpt4↑, MMP2↑, MMP9↑, NOS3↑, NPC2↑, P2RX4↑, PAK1↑, PLVAP↑, PLXNB2↑, POFUT1↑, PROCR↑, PTGES↑, S100A4↑, SERPINH1↑, SGPL1↑, STAT3↑, THRAP3↑, TKT↑, GTF2I↓, HRAS↓, ICAM1↓, SMOC2↓ | 47 |
Angiogenesis (3.63E-06) | 2.855 ▲ | ABI1↑, ADD1↑, ANXA1↑, APOE↑, CASP3↑, CD34↑, COL4A1↑, COMMD1↑, CYBA↑, CYBB↑, EMILIN1↑, F11R↑, FLNA↑, G6PD↑, GLUL↑, HLA-DQB1↑, HSPB1↑, HSPB6↑, HSPG2↑, IGFBP7↑, LAMA4↑, LGALS3↑, LRP1↑, Mcpt4↑, MMP2↑, MMP9↑, NOS3↑, PAK1↑, PLVAP↑, POFUT1↑, PROCR↑, PTGES↑, S100A4↑, SERPINH1↑, SGPL1↑, STAT3↑, THRAP3↑, TKT↑, GTF2I↓, HRAS↓, ICAM1↓, SMOC2↓ | 42 | |
Vasculogenesis (1.21E-05) | 2.575 ▲ | ABI1↑, ANXA1↑, APOE↑, CASP3↑, CD34↑, COL4A1↑, COMMD1↑, CYBA↑, CYBB↑, F11R↑, FLNA↑, G6PD↑, GLUL↑, HLA-DQB1↑, HSPG2↑, IGFBP7↑, LGALS3↑, LRP1↑, Mcpt4↑, MMP2↑, MMP9↑, NOS3↑, PAK1↑, PLVAP↑, POFUT1↑, PROCR↑, S100A4↑, SERPINH1↑, SGPL1↑, STAT3↑, THRAP3↑, TKT↑, HRAS↓, ICAM1↓, SMOC2↓ | 35 | |
Cell Death and Survival | Apoptosis (1.56E-06) | −2.602 ▼ | ACACA↑, ACLY↑, ALDH3A1↑, ANXA1↑, APOE↑, ARF4↑, ARL6IP1↑, ASAH1↑, ASNS↑, BASP1↑, CASP3↑, CASP6↑, COL4A1↑, CTSZ↑, CYBA↑, CYBB↑, CYP2F1↑, DDX58↑, DPM3↑, DTYMK↑, ELMO1↑, EMILIN2↑, ERC1↑, Ewsr1↑, FAH↑, FASN↑, FLNA↑, G6PD↑, GMDS↑, HLA-DQB1↑, HRAS↓, HSPB1↑, HSPB6↑, HSPG2↑, IGFBP7↑, ILF3↑, IQGAP2↑, IRF2BP2↑, Irgm1↑, LAMA4↑, LGALS3↑, LGALS7/LGALS7B↑, LGMN↑, LIMS1↑, LRP1↑, LSP1↑, Mcpt4↑, MMP2↑, MMP9↑, Mt2↑, MTA2↑, NELFB↑, NFKB2↑, NOS3↑, P2RX4↑, PAK1↑, PEX11B↑, PPP1R9B↑, PRKAR2B↑, PRMT1↑, PROCR↑, PRTN3↑, PTGES↑, RAB32↑, S100A10↑, S100A4↑, SCD↑, SEL1L↑, SERPINB1↑, SERPINH1↑, SET↑, SGPL1↑, SIRPA↑, SLC25A10↑, SLC25A5↑, SNX1↑, SRI↑, SRSF2↑, STAT3↑, SWAP70↑, TARDBP↑, TRIM28↑, UBA2↑, WDR5↑, XRCC5↑, ICAM1↓, IFIT2↓, MAPK12↓, NQO1↓, PAFAH1B3↓, TIGAR↓ | 91 |
Cell survival (7.27E-04) | 3.789 ▲ | ACACA↑, ACLY↑, APOE↑, ASAH1↑, ASNS↑, CASP3↑, CASP6↑, CYBA↑, CYBB↑, EMILIN2↑, FASN↑, FLNA↑, GALK2↑, GIT1↑, GPNMB↑, HLA-A↑, HNRNPU↑, HSPB1↑, HSPB6↑, IGFBP7↑, LGALS3↑, LGALS7/LGALS7B↑, LIMS1↑, LRP1↑, MCFD2↑, MGST1↑, MMP9↑, Mt2↑, NFKB2↑, NOS3↑, PAK1↑, POSTN↑, PRMT1↑, PRTN3↑, PSME3↑, S100A4↑, SCD↑, SEL1L↑, SET↑, SGPL1↑, SHMT2↑, STAT3↑, TARDBP↑, THRSP↑, TRIM28↑, XRCC5↑, HRAS↓, ICAM1↓, MAPK12↓, SMC1A↓ | 50 | |
Cellular Movement | Cell movement (1.03E-09) | 4.746 ▲ | ABI1↑, ACACA↑, ADD1↑, ANXA1↑, APBB1IP↑, APOE↑, ARF4↑, ARFGAP3↑, ARPC1B↑, ASNS↑, BIN2↑, CAP1↑, CD34↑, CD93↑, CLIC1↑, COL4A1↑, COMMD5↑, CORO1C↑, CTSZ↑, CYBB↑, DDX58↑, ELMO1↑, EMILIN2↑, ERC1↑, EVL↑, F11R↑, FABP5↑, FASN↑, FHL3↑, FLNA↑, FLNC↑, FSCN1↑, G6PD↑, GIT1↑, GIT2↑, GLUL↑, GPNMB↑, HLA-A↑, HNRNPA2B1↑, HSPB1↑, HSPG2↑, IFITM3↑, IGFBP7↑, ILF3↑, Irgm1↑, LAMA4↑, LCP1↑, LGALS3↑, LGMN↑, LIMS1↑, LIPE↑, LRP1↑, LSP1↑, Mcpt4↑, MMP2↑, MMP9↑, MRC2↑, Mt2↑, NAAA↑, NDUFAF3↑, NFKB2↑, NOS3↑, P2RX4↑, PAK1↑, PEX11B↑, PLXNB2↑, POSTN↑, PPP1R9B↑, PRMT1↑, PROCR↑, PRTN3↑, PTGES↑, RGS10↑, S100A10↑, S100A4↑, SERPINB1↑, SERPINH1↑, SGPL1↑, SIRPA↑, STAT3↑, SWAP70↑, TARDBP↑, TKT↑, GTF2I↓, HRAS↓, ICAM1↓, IFIT2↓, MAPK12↓, NNMT↓, NQO1↓, SMOC2↓, Tpm1↓, TPM3↓ | 93 |
Cell Migration (1.17E-07) | 4.562 ▲ | ACACA↑, ADD1↑, ANXA1↑, APBB1IP↑, APOE↑, ARF4↑, ARFGAP3↑, ASNS↑, CAP1↑, CD34↑, CD93↑, COL4A1↑, COMMD5↑, CORO1C↑, CTSZ↑, CYBB↑, DDX58↑, ELMO1↑, EMILIN2↑, ERC1↑, EVL↑, F11R↑, FABP5↑, FASN↑, FLNA↑, FLNC↑, FSCN1↑, G6PD↑, GIT1↑, GIT2↑, GLUL↑, GPNMB↑, HLA-A↑, HNRNPA2B1↑, HSPB1↑, IFITM3↑, IGFBP7↑, ILF3↑, Irgm1↑, LAMA4↑, LCP1↑, LGALS3↑, LGMN↑, LRP1↑, LSP1↑, Mcpt4↑, MMP2↑, MMP9↑, MRC2↑, NAAA↑, NFKB2↑, NOS3↑, P2RX4↑, PAK1↑, PEX11B↑, PLXNB2↑, POSTN↑, PPP1R9B↑, PRMT1↑, PROCR↑, PRTN3↑, PTGES↑, S100A10↑, S100A4↑, SERPINB1↑, SGPL1↑, SIRPA↑, STAT3↑, SWAP70↑, TARDBP↑, HRAS↓, ICAM1↓, IFIT2↓, MAPK12↓, NDUFAF3↓, NNMT↓, NQO1↓, SMOC2↓, Tpm1↓, TPM3↓ | 80 | |
Chemotaxis (5.15E-07) | 2.773 ▲ | ANXA1↑, APOE↑, BIN2↑, CYBB↑, ELMO1↑, GIT1↑, GIT2↑, LCP1↑, LGALS3↑, LGMN↑, LRP1↑, LSP1↑, MMP2↑, MMP9↑, Mt2↑, NFKB2↑, NOS3↑, P2RX4↑, PAK1↑, PRTN3↑, PTGES↑, RGS10↑, S100A4↑, SERPINB1↑, SERPINH1↑, SIRPA↑, STAT3↑, SWAP70↑ HRAS↓, ICAM1↓ | 30 |
SE/SC | SF/SC | Proteins | Functions |
---|---|---|---|
↑ | ↑ | LSMEM1 | Necrosis ▲ Apoptosis ▲ Atherosclerosis ▬ Neovascularization ▬ Angiogenesis ▼ Vasculature Development ▼ Endothelial cell development ▲ Endothelial cell Proliferation▲ |
↓ | ↓ | AACS, ALDH3A1, ATP2B4, BPHL, BTF3L4, CASQ2, CAV1, CAV3, CD99, CDC5L, CILP, CKAP5, COX6A1, CREG1, FAU, FHL1, FLG, GAMT, GCDH, GM8210, GPC1, GPNMB, HDGFL2, HSPB6, HSPB7, IFI30, IRF2BPL, KLHL41, LAMP2, LGALS3, MAN2B2, MAP3K20, MCAM, MRPL12, MRPS5, MRPS27, MTCH1, MYL4, MYL6B, NES, PLOD2, PRKG1, RBBP6, RPLP1, RPL13, RPL17, RPL21, RPL35, RPL37A, RPS17, S100A11, SCD1, SPARC, SEC16A, SPRR1A, SLMAP, SERPINF1, SERPINB6A, SERF2, SNRPD2, STMN1, TGTP1, TNC, TMEM167, TPP1, XIRP1 | |
↑ | - | ABCA1, APAF1, APBB1IP, APOBR, ARG2, ARL6IP1, ASS1, BC017643, CAPZA1, CAR13, CASP8, CD14, CYBB, DCAKD, DDX39, DHFR, DR1, DTYMK, ELANE, ELMO1, EMB, EMILIN1, EMILIN2, GCN1L1, GFPT1, GIT2, H2AFY, HMOX1, HVM22, IFIH1, IFIT1, IFIT2, IGHV5-4, IGJ, IGKV12-44, IGKV12-47, IGKV14-111, IL1RN, IQGAP2, ITGB2, LGALS7, LGALS9, LOC433053, LSP1, MOGS, MPO, MSR1, NAPSA, NCF1, NCF2, NCKAP1L, PLBD1, PLIN2, PRPF40A, P2RX4, PRTN3, PSTPIP1, PTGES, PTPN1, RETNLG, ROD1, SAA4, SDF2L1, SEL1L, SKAP2, SNX18, SPCS3, SLC9A3R1, SRC, STFA1, STS, SUN2, SUPT16H, TAP1, TBL2, VAV1, WASF2 | Apoptosis ▲ Atherosclerosis ▲ Angiogenesis Vasculature Development ▬ Vasculogenesis ▬ Atherogenesis ▬ Activation of cells ▲ Cell movement ▲ Immune response of cells ▲ |
↓ | - | ABHD5, ACADS, ACAT2, ACLY, ALDH2, ALDH1A7, ALDH1L1, ALDH4A1, CAR5B, CES1D, CES1F, COMP, COX8B, 4931406C07RIK, CRABP1, CRYAB, CSAD, CSRP3, CYP2E1, DNAJA4, ECHDC1, EPHX2, FABP4, FAH, FASN, GADD45GIP1, G3BP2, GLUL, GNAI1, GSTA3, GSTZ1, HDHD3, KLHL40, KRT10, LIPE, ME1, MGLL, MRPL11, MRPL41, MRPL53, NRAP, PCBD1, PCX, PDLIM1, PTGES3L, PTMS, PLIN1, RBP7, SEPT4, SSC5D, SLC25A1, THRSP, THBS4, TST, YAP1 | |
- | ↑ | None | Necrosis ▲ Apoptosis ▲ PAD ▬ Diabetes mellitus ▬ Cell Activation ▼ Cell Attachment ▼ Cell movement ▼ Cell Migration ▼ Cell Outgrowth ▼ Lipid Accumulation ▲ Quantity of IFN in blood ▲ |
- | ↓ | ACOT9, ACOX1, ACP2, ACTB, ACTN1, ACTN2, ACTN4, ADIPOQ, ADPRHL2, AIF1, ALDH16A1, ANKFY1, ANO6, AMDHD2, AMY1, APCS, AP1M1, AP2M1, APOBEC2, APOD, APOE, ARHGDIB, ARPIN, ARPC5, ART3, BASP1, BGN, BIN2, B2M, CACNG1, CD44, CDH13, CFH, CKAP4, CLTC, CNN2, COA7, COL1A2, COL12A1, COL14A1, COLGALT1, COPA, COPB1, COPE, COPG1, COPG2, CORO1C, COTL1, CSK, CTSA, CTSC, CTSD, CTSH, CTSZ, DCLK1, DCUN1D2, DDOST, DDX5, DHX15, DNM3, DNPEP, DYNC1H1, EEF1AKMT1, EEF1B2, EFEMP1, EIF4A3, EIF3E, EIF3L, EFHD2, EHD2, EHD4, ERGIC3, ERO1LB, ERP29, ETF1, ETFDH, EVL, FKBP15, FN1, GC, GLA, GM5571, GMFB, GMPR2, GSTT1, GSTT3, GUSB, H2-AA, H2-AB1, H2AFV, HAL, H2-D1, H2-EB1, HEXB, HIST1H4A, HIST1H2BB, HNRNPC, HPRT, HRG, HSPB2, HYPK, IFI204, IFI211, IFI44L, IGHG, IGHG3, IGHV2-3, IIGP1B, IQGAP1, IRGM1, ISG15, ITGA6, ITGB4, JPT1, LAMTOR5, LCP1, LGALS3BP, LGMN, LIPA, LMNA, LRRC59, LXN, MAN2A1, MAN2B1, MARCKSL1, MBL1, ME2, MFF, MMP9, MPZ, MYH7, MYL6, MYO1C, NAA15, NAA20, NAP1L1, NCAM1, NDUFB6, NGLY1, NGP, ORM2, OST4, PACSIN3, PAPSS2, PCNA, PDXK, PEA15A, PIGS, PMP2, POSTN, PPIC, PP1R14B, PPP1R14C, PRCP, PRDX4, PRX, PSMB10, PSMC1, PTRH2, PYCARD, RAB12, RACK1, RCC2, RCN3, RENBP, RNF213, RPA3, RPL3, RPL4, RPL5, RPL6, RPL7, RPL8, RPL9, RPL10A, RPL11, RPL12, RPL13A, RPL14, RPL15, RPL7A, RPL18, RPL22, RPL23, RPL23A, RPL24, RPL26, RPL27, RPL27A, RPL28, RPL36, RPLP0, RPLP2, RPL32P, RPL10-PS1, RPL19-PS11, RPL34-PS1, RPL36A-PS3, RPS2, RPS3, RPS5, RPS7, RPS8, RPS9, RPS10, RPS11, RPS14, RPS18, RPS19, RPS20, RPS21, RPS25, RPS28, RPS29, RPS15A, RPSA, RPS3A1, RPS2-PS13, RPS13-PS1, RPS26-PS1, RPS6-PS4, RPS16-PS2, RPS4X, RTCB, S100A4, SCAMP1, SCAMP3, SEPT5, SF3B5, SF3B6, SFN, SH3BGRL3, SIRPA, SLN, SNRPF, SH3BGRL, SNRPD3, SPATA7, SRSF2, SRSF1, SRSF5, SSR4, STARD7, STEAP3, STOM, SUB1, SULT1A1, SYNC, SYNGR2, TANGO2, TAPT1, THY1, TNNC1, TNNT3, TMED9, TM9SF3, TPD52, TRIM72, TUBA1A, TUBB2A, TUBB5, TWF2, UCHL1, UFM1, UFSP2, UPP1, VAT1, VPS29, WDR82, ZBP1 | |
↑ | ↓ | ADGRE1, ALDH1B1, ALOX5AP, AOAH, AP3D1, ARG1, CAD, C5AR1, CD48, CD68, CD180, CEP170, CPT1A, C1QTNF3, C1S1, CTSG, CTSS, CYBA, DDX58, DNAJB11, DNASE2A, FYB, GALK2, GSDMD, H13, HEXA, HK3, IFI44, ITGAM, KDELR2, LBR, MAGOHB, MFSD1, MPEG1, MYL12B, NCF4, OLFM4, PARVG, PHF11D, PLA2G15, PLD4, PLEK, PRPF8, PRRC2A, PTPN6, PTPRC, RAB32, S100A8, SEC11A, SEC61A1, SP100, SRGAP2, STAT1, STAT2, SYK, TAPBP, TAP2, TMED3, TOR3A, TOP2A, STFA3, UGT1A7C, U2SURP | Angiogenesis ▲ Diabetes mellitus ▬ Cell Activation ▲ Cells movement ▲ Immune response of cells ▲ Cell Degranulation ▲ |
↓ | ↑ | None |
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Beltrán-Camacho, L.; Jiménez-Palomares, M.; Sanchez-Gomar, I.; Rosal-Vela, A.; Rojas-Torres, M.; Eslava-Alcon, S.; Alonso-Piñero, J.A.; González-Rovira, A.; Extremera-García, M.J.; Conejero, R.; et al. Long Term Response to Circulating Angiogenic Cells, Unstimulated or Atherosclerotic Pre-Conditioned, in Critical Limb Ischemic Mice. Biomedicines 2021, 9, 1147. https://doi.org/10.3390/biomedicines9091147
Beltrán-Camacho L, Jiménez-Palomares M, Sanchez-Gomar I, Rosal-Vela A, Rojas-Torres M, Eslava-Alcon S, Alonso-Piñero JA, González-Rovira A, Extremera-García MJ, Conejero R, et al. Long Term Response to Circulating Angiogenic Cells, Unstimulated or Atherosclerotic Pre-Conditioned, in Critical Limb Ischemic Mice. Biomedicines. 2021; 9(9):1147. https://doi.org/10.3390/biomedicines9091147
Chicago/Turabian StyleBeltrán-Camacho, Lucía, Margarita Jiménez-Palomares, Ismael Sanchez-Gomar, Antonio Rosal-Vela, Marta Rojas-Torres, Sara Eslava-Alcon, Jose Angel Alonso-Piñero, Almudena González-Rovira, Mª Jesús Extremera-García, Rosario Conejero, and et al. 2021. "Long Term Response to Circulating Angiogenic Cells, Unstimulated or Atherosclerotic Pre-Conditioned, in Critical Limb Ischemic Mice" Biomedicines 9, no. 9: 1147. https://doi.org/10.3390/biomedicines9091147