Atherosclerosis (AS) is a chronic inflammatory disease associated with lipid deposition, which could be converted into acute clinical events by thrombosis or plaque rupture. Adipose-derived mesenchymal stem cell (ADSC)-encapsulated repair units could be an effective cure for the treatment of AS patients. In this study, we encapsulate human adipose-derived mesenchymal stem cells (hADSCs) in collagen microspheres to fabricate stem cell repair units. Besides, we show that encapsulation in collagen microspheres and cultured in vitro for 14 days maintain the viability and stemness of hADSCs. Moreover, we generate AS progression model and niche in vitro by combining hyperlipemia serum of AS patients with AS cell models. We further systematically demonstrate that hADSC-based microspheres could ameliorate AS progression by inhibiting oxidative stress injury, cell apoptosis, endothelial dysfunction, inflammation, and lipid accumulation. In addition, we perform transcriptomic analysis and functional studies to demonstrate how hADSCs (three dimensional cultured in microspheres) respond to AS niche compared with healthy microenvironment. These findings reveal a role for ADSC-based microspheres in the treatment of AS and provide new ideas for stem cell therapy in cardiovascular disease. The results may have implications for improving the efficiency of hADSC therapies by illuminating the mechanisms of hADSCs exposed in special pathological niche.
Get full access to this article
View all access options for this article.
References
1.
Lusis AJ. (2000). Atherosclerosis. Nature, 407:233–241.
2.
Björkegren JLM and LusisAJ. (2022). Atherosclerosis: recent developments. Cell, 185:1630–1645.
3.
RoyP, OrecchioniM and LeyK. (2022). How the immune system shapes atherosclerosis: roles of innate and adaptive immunity. Nat Rev Immunol, 22:251–265.
4.
ZhangN, XieX, ChenH, ChenH, YuH and JAWang. (2014). Stem cell-based therapies for atherosclerosis: perspectives and ongoing controversies. Stem Cells Dev, 23:1731–1740.
5.
BrownC, McKeeC, BakshiS, WalkerK, HakmanE, HalassyS, SvinarichD, DoddsR, GovindCK and ChaudhryGR. (2019). Mesenchymal stem cells: cell therapy and regeneration potential. J Tissue Eng Regen Med, 13:1738–1755.
6.
BaileyAM, MendicinoM and AuP. (2014). An FDA perspective on preclinical development of cell-based regenerative medicine products. Nat Biotechnol, 32:721–723.
7.
SamsonrajRM, RaghunathM, NurcombeV, HuiJH, van WijnenAJ and CoolSM. (2017). Concise review: multifaceted characterization of human mesenchymal stem cells for use in regenerative medicine. Stem Cells Transl Med, 6:2173–2185.
8.
MinteerD, MarraKG and RubinJP. (2013). Adipose-derived mesenchymal stem cells: biology and potential applications. Adv Biochem Eng Biotechnol, 129:59–71.
9.
FodorPB and PaulsethSG. (2016). Adipose derived stromal cell (ADSC) injections for pain management of osteoarthritis in the human knee joint. Aesthet Surg J, 36:229–236.
10.
SquassoniSD, SekiyaEJ, FissE, LapaMS, CayetanoDDS, NascimentoF, AlvesA, MachadoNC, EscaramboniB, et al. (2021). Autologous infusion of bone marrow and mesenchymal stromal cells in patients with chronic obstructive pulmonary disease: phase I randomized clinical trial. Int J Chron Obstruct Pulmon Dis, 16:3561–3574.
11.
KirwinT, GomesA, AminR, SufiA, GoswamiS and WangB. (2021). Mechanisms underlying the therapeutic potential of mesenchymal stem cells in atherosclerosis. Regen Med, 16:669–682.
12.
TakafujiY, HoriM, MizunoT and Harada-ShibaM. (2019). Humoral factors secreted from adipose tissue-derived mesenchymal stem cells ameliorate atherosclerosis in Ldlr-/- mice. Cardiovasc Res, 115:1041–1051.
13.
YuS, ChengY, ZhangL, YinY, XueJ, LiB, GongZ, GaoJ and MuY. (2019). Treatment with adipose tissue-derived mesenchymal stem cells exerts anti-diabetic effects, improves long-term complications, and attenuates inflammation in type 2 diabetic rats. Stem Cell Res Ther, 10:333.
14.
SuN, GaoPL, WangK, WangJY, ZhongY and LuoY. (2017). Fibrous scaffolds potentiate the paracrine function of mesenchymal stem cells: a new dimension in cell-material interaction. Biomaterials, 141:74–85.
15.
CarterK, LeeHJ, NaKS, Fernandes-CunhaGM, BlancoIJ, DjalilianA and MyungD. (2019). Characterizing the impact of 2D and 3D culture conditions on the therapeutic effects of human mesenchymal stem cell secretome on corneal wound healing in vitro and ex vivo. Acta Biomater, 99:247–257.
16.
DesaiT and SheaLD. (2017). Advances in islet encapsulation technologies. Nat Rev Drug Discov, 16:338–350.
17.
SorushanovaA, DelgadoLM, WuZ, ShologuN, KshirsagarA, RaghunathR, MullenAM, BayonY, PanditA, RaghunathM and ZeugolisDI. (2019). The collagen suprafamily: from biosynthesis to advanced biomaterial development. Adv Mater, 31:e1801651.
18.
YangS, JiangX, XiaoX, NiuC, XuY, HuangZ, KangYJ and FengL. (2021). Controlling the poly(epsilon-caprolactone) degradation to maintain the stemness and function of adipose-derived mesenchymal stem cells in vascular regeneration application. Macromol Biosci, 21:e2000226.
19.
LiF, GuoX and ChenSY. (2017). Function and therapeutic potential of mesenchymal stem cells in atherosclerosis. Front Cardiovasc Med, 4:32.
20.
Tabatabaei Qomi R and SheykhhasanM. (2017). Adipose-derived stromal cell in regenerative medicine: a review. World J Stem Cells, 9:107–117.
21.
GalipeauJ and SensébéL. (2018). Mesenchymal stromal cells: clinical challenges and therapeutic opportunities. Cell Stem Cell, 22:824–833.
22.
WangH, LiangX, XuZP, CrawfordDH, LiuX and RobertsMS. (2016). A physiologically based kinetic model for elucidating the in vivo distribution of administered mesenchymal stem cells. Sci Rep, 6:22293.
23.
EggenhoferE, BenselerV, KroemerA, PoppFC, GeisslerEK, SchlittHJ, BaanCC, DahlkeMH and HoogduijnMJ. (2012). Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol, 3:297.
24.
KaleVP. (2019). Application of “Primed” mesenchymal stromal cells in hematopoietic stem cell transplantation: current status and future prospects. Stem Cells Dev transplantation:1473–1479.
25.
KimAK, KimMH, KimDH, GoHN, ChoSW, UmSH and KimDI. (2016). Inhibitory effects of mesenchymal stem cells in intimal hyperplasia after balloon angioplasty. J Vasc Surg, 63:510–517.
26.
CesarzZ and TamamaK. (2016). Spheroid culture of mesenchymal stem cells. Stem Cells Int, 2016:9176357.
27.
FuentesP, TorresMJ, ArancibiaR, AulestiaF, VergaraM, CarrionF, OssesN and AltamiranoC. (2022). Dynamic culture of mesenchymal stromal/stem cell spheroids and secretion of paracrine factors. Front Bioeng Biotechnol, 10:916229.
28.
KattoorAJ, KanuriSH and MehtaJL. (2019). Role of Ox-LDL and LOX-1 in atherogenesis. Curr Med Chem, 26:1693–1700.
29.
MiaoJ, ZangX, CuiX and ZhangJ. (2020). Autophagy, hyperlipidemia, and atherosclerosis. Adv Exp Med Biol, 1207:237–264.
30.
SobeninIA, ChistiakovDA, BobryshevYV and OrekhovAN. (2013). Blood atherogenicity as a target for anti-atherosclerotic therapy. Curr Pharm Des, 19:5954–5962.
31.
BrescianiG, da CruzIB and González-GallegoJ. (2015). Manganese superoxide dismutase and oxidative stress modulation. Adv Clin Chem, 68:87–130.
32.
TsikasD. (2017). Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: analytical and biological challenges. Anal Biochem, 524:13–30.
YangM and SilversteinRL. (2019). CD36 signaling in vascular redox stress. Free Radic Biol Med, 136:159–171.
35.
de NigrisF, LermanA, IgnarroLJ, Williams-IgnarroS, SicaV, BakerAH, LermanLO, GengYJ and NapoliC. (2003). Oxidation-sensitive mechanisms, vascular apoptosis and atherosclerosis. Trends Mol Med, 9:351–359.
36.
PanF, LiaoN, ZhengY, WangY, GaoY, WangS, JiangY and LiuX. (2015). Intrahepatic transplantation of adipose-derived stem cells attenuates the progression of non-alcoholic fatty liver disease in rats. Mol Med Rep, 12:3725–3733.
37.
FanM, BaiJ, DingT, YangX, SiQ and NieD. (2019). Adipose-derived stem cell transplantation inhibits vascular inflammatory responses and endothelial dysfunction in rats with atherosclerosis. Yonsei Med J, 60:1036–1044.
38.
ZhaoH, ShangQ, PanZ, BaiY, LiZ, ZhangH, ZhangQ, GuoC, ZhangL and WangQ. (2018). Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and beiging in white adipose tissue. Diabetes, 67:235–247.
39.
SouilholC, HarmsenMC, EvansPC and KrenningG. (2018). Endothelial-mesenchymal transition in atherosclerosis. Cardiovasc Res, 114:565–577.
40.
LiM, JiangY, HouQ, ZhaoY, ZhongL and FuX. (2022). Potential pre-activation strategies for improving therapeutic efficacy of mesenchymal stem cells: current status and future prospects. Stem Cell Res Ther, 13:146.
41.
VaisarT, TangC, BabenkoI, HutchinsP, WimbergerJ, SuffrediniAF and HeineckeJW. (2015). Inflammatory remodeling of the HDL proteome impairs cholesterol efflux capacity. J Lipid Res, 56:1519–1530.
42.
LiuZ, ChangAN, GrinnellF, TrybusKM, MilewiczDM, StullJT and KammKE. (2017). Vascular disease-causing mutation, smooth muscle α-actin R258C, dominantly suppresses functions of α-actin in human patient fibroblasts. Proc Natl Acad Sci U S A, 114:E5569–e5578.
43.
TsukamotoK, ManiDR, ShiJ, ZhangS, HaagensenDE, OtsukaF, GuanJ, SmithJD, WengW, et al. (2013). Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease. Proc Natl Acad Sci U S A, 110:17023–17028.
44.
YamadaY, SakumaJ, TakeuchiI, YasukochiY, KatoK, OguriM, FujimakiT, HoribeH, MuramatsuM, et al. (2017). Identification of rs7350481 at chromosome 11q23.3 as a novel susceptibility locus for metabolic syndrome in Japanese individuals by an exome-wide association study. Oncotarget, 8:39296–39308.
DoehnerW, von HaehlingS, SuhrJ, EbnerN, SchusterA, NagelE, MelmsA, WursterT, StellosK, GawazM and BigalkeB. (2012). Elevated plasma levels of neuropeptide proenkephalin a predict mortality and functional outcome in ischemic stroke. J Am Coll Cardiol, 60:346–354.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
