Restricted accessResearch articleFirst published online 2021-11
Characterization of Urine-Derived Stem Cells from Patients with End-Stage Liver Diseases and Application to Induced Acute and Chronic Liver Injury of Nude Mice Model
Urine-derived stem cells (USCs) are adult stem cells isolated from urine with strong proliferative ability and differentiation potentials. Cell transplantation of USCs could partly repair liver injury. It has been reported that the proliferative ability of bone mesenchymal stem cells in patients with chronic liver failure is significantly lower than in patients without liver disease. The aim of this study was therefore to evaluate the biological characteristics of USCs from end-stage liver disease patients (LD-USCs, USCs from patients with liver disease) compared with those from normal healthy individuals (N-USCs, USCs from normal individuals), with a view to determining whether autologous USCs can be applied to the treatment of liver disease. In this study USCs were isolated from urine samples of male patients with end-stage liver disease. Adherent USCs exhibit a spindle- or rice grain-like morphology, and express CD24, CD29, CD73, CD90, and CD146 surface markers, but not CD31, CD34, CD45, and CD105. We observed no differences in cell morphology or cell surface marker profile between LD-USCs and N-USCs. LD-USCs exhibited similar proliferative, colony-forming, apoptotic, and migratory abilities to N-USCs. Both USCs demonstrated similar capacities for osteogenic, adipogenic, and chondrogenic differentiation. When USCs were transplanted into CCl4 treatment-induced acute and chronic liver fibrosis mouse models, we observed a decrease in liver index, recovery of alanine aminotransferase and aspartate aminotransferase levels, alleviation of liver tissue injury, and dramatic improvement of liver tissue structure. USC transplantation can effectively recover liver function and improve liver tissue damage in acute or chronic liver injury mouse models. According to the results, we concluded that the biological characteristics of LD-USCs are not affected by basic liver disease. This study provides further evidence of the stem cell characteristics and liver repair function of LD-USCs, which may serve as a theoretical and experimental foundation for autologous USC transplantation technology in the treatment of liver failure and end-stage liver diseases.
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References
1.
Duarte-RojoA, Ruiz-MargáinA, Montaño-LozaAJ, Macías-RodríguezRU, FerrandoA and KimWR. (2018). Exercise and physical activity for patients with end-stage liver disease: improving functional status and sarcopenia while on the transplant waiting list. Liver Transpl, 24:122–139.
2.
SamoylovaML, CovinskyKE, HaftekM, KuoS, RobertsJP and LaiJC. (2017). Disability in patients with end-stage liver disease: results from the functional assessment in liver transplantation study. Liver Transpl, 23:292–298.
3.
CharltonM, LevitskyJ, AqelB, O'GradyJ, HemibachJ, RinellaM, FungJ, GhabrilM, ThomasonR, et al. (2018). International liver transplantation society consensus statement on immunosuppression in liver transplant recipients. Transplantation, 102:727–743.
4.
JadlowiecCC and TanerT. (2016). Liver transplantation: current status and challenges. World J Gastroenterol, 22:4438–4445.
5.
DhanasekaranR. (2017). Management of immunosuppression in liver transplantation. Clin Liver Dis, 21:337–353.
6.
ForbesSJ, GuptaS and DhawanA. (2015). Cell therapy for liver disease: from liver transplantation to cell factory. J Hepatol, 62:S157–S169.
7.
LeeCA, SinhaS, FitzpatrickE and DhawanA. (2018). Hepatocyte transplantation and advancements in alternative cell sources for liver-based regenerative medicine. J Mol Med (Berl), 96:469–481.
8.
ZakrzewskiW, DobrzyńskiM, SzymonowiczM and RybakZ. (2019). Stem cells: past, present, and future. Stem Cell Res Ther, 10:68.
9.
WangJ, SunM, LiuW, LiY and LiM. (2019). Stem cell-based therapies for liver diseases: an overview and update. Tissue Eng Regen Med, 16:107–118.
10.
MessinaA, LuceE, HusseinM and Dubart-KupperschmittA. (2020). Pluripotent-stem-cell-derived hepatic cells: hepatocytes and organoids for liver therapy and regeneration. Cells, 9:420.
11.
SamadiP, SakiS, ManoochehriH and Sheykhhasan.M Therapeutic applications of mesenchymal stem cells: a comprehensive review. Curr Stem Cell Res Ther 16:323–353.
12.
ZhangS, YangY, FanL, ZhangF and LiL. (2020). The clinical application of mesenchymal stem cells in liver disease: the current situation and potential future. Ann Transl Med, 8:565.
13.
LanzaR, RussellDW and NagyA. (2019). Engineering universal cells that evade immune detection. Nat Rev Immunol, 19:723–733.
14.
CalderonD, ProtM, YouS, MarquetC, BellamyV, BrunevalP, ValetteF, de AlmeidaP, WuJC, et al. (2016). Control of immune response to allogeneic embryonic stem cells by CD3 antibody-mediated operational tolerance induction. Am J Transplant, 16:454–467.
15.
ZhangY, McNeillE, TianH, SokerS, AnderssonKE, YooJJ and AtalaA. (2008). Urine derived cells are a potential source for urological tissue reconstruction. J Urol, 180:2226–2233.
16.
BurdeyronP, GiraudS, HauetT and SteichenC. (2020). Urine-derived stem/progenitor cells: a focus on their characterization and potential. World J Stem Cells, 12:1080–1096.
17.
Pavathuparambil Abdul ManaphN, Al-HawwasM, BobrovskayaL, CoatesPT and ZhouXF. (2018). Urine-derived cells for human cell therapy. Stem Cell Res Ther, 9:189.
18.
XingF, LiL, SunJ, LiuG, DuanX, ChenJ, LiuM, LongY and XiangZ. (2019). Surface mineralized biphasic calcium phosphate ceramics loaded with urine-derived stem cells are effective in bone regeneration. J Orthop Surg Res, 14:419.
19.
ZhangC, GeorgeSK, WuR, ThakkerPU, AbolbashariM, KimTH, KoIK, ZhangY, SunY, et al. (2020). Reno-protection of urine-derived stem cells in a ahronic kidney disease rat model induced by renal ischemia and nephrotoxicity. Int J Biol Sci, 16:435–446.
20.
JinY, YangL, ZhangY, GaoW, YaoZ, SongY and WangY. (2017). Effects of age on biological and functional characterization of adipose-derived stem cells from patients with end-stage liver disease. Mol Med Rep, 16:3510–3518.
21.
ChunSY, KimHT, LeeJS, KimMJ, KimBS, KimBW and KwonTG. (2012). Characterization of urine-derived cells from upper urinary tract in patients with bladder cancer. Urology, 79:1186.e1–e7.
22.
DominiciM, Le BlancK, MuellerI, Slaper-CortenbachI, MariniF, KrauseD, DeansR, KeatingA, ProckopD and HorwitzE. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8:315–317.
23.
BourinP, BunnellBA, CasteillaL, DominiciM, KatzAJ, MarchKL, RedlH, RubinJP, YoshimuraK and GimbleJM. (2013). Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy, 15:641–648.
24.
Nguyen-LefebvreAT, AjithA, Portik-DobosV, HoruzskoDD, ArbabAS, DzutsevA, SadekR, TrinchieriG and HoruzskoA. (2018). The innate immune receptor TREM-1 promotes liver injury and fibrosis. J Clin Invest, 128:4870–4883.
25.
HuC, HeY, FangS, TianN, GongM, XuX, ZhaoL, WangY, HeT, ZhangY and BiY. (2020). Urine-derived stem cells accelerate the recovery of injured mouse hepatic tissue. Am J Transl Res, 12:5131–5150.
26.
TaoYC and ChenEQ. (2020). Clinical application of stem cell in patients with end-stage liver disease: progress and challenges. Ann Transl Med, 8:564.
27.
Lagarkova MA. (2019). Such various stem cells. Biochemistry (Mosc), 84:187–189.
28.
DulakJ, SzadeK, SzadeA, NowakW and JózkowiczA. (2015). Adult stem cells: hopes and hypes of regenerative medicine. Acta Biochim Pol, 62:329–337.
29.
BozdağSC, YükselMK and DemirerT. (2018). Adult stem cells and medicine. Adv Exp Med Biol, 1079:17–36.
30.
MaH, WertKJ, ShvartsmanD, MeltonDA and JaenischR. (2018). Establishment of human pluripotent stem cell-derived pancreatic β-like cells in the mouse pancreas. Proc Natl Acad Sci U S A, 115:3924–3929.
31.
VeltriA, LangC and LienWH. (2018). Concise review: Wnt signaling pathways in skin development and epidermal stem cells. Stem Cells, 36:22–35.
32.
WuC, ChenL, HuangYZ, HuangY, ParoliniO, ZhongQ, TianX and DengL. (2018). Comparison of the proliferation and differentiation potential of human urine-, placenta decidua basalis-, and bone marrow-derived stem cells. Stem Cells Int, 2018:7131532.
33.
SunJ, XingF, ZouM, GongM, LiL and XiangZ. (2021). Comparison of chondrogenesis-related biological behaviors between human urine-derived stem cells and human bone marrow mesenchymal stem cells from the same individual. Stem Cell Res Ther, 12:366.
34.
KangHS, ChoiSH, KimBS, ChoiJY, ParkGB, KwonTG and ChunSY. (2015). Advanced properties of urine derived stem cells compared to adipose tissue derived stem cells in terms of cell proliferation, immune modulation and multi differentiation. J Korean Med Sci, 30:1764–1776.
35.
Ruiz-BabotG, BalyuraM, HadjidemetriouI, AjodhaSJ, TaylorDR, GhataoreL, TaylorNF, SchubertU, ZieglerCG, et al. (2018). Modeling congenital adrenal hyperplasia and testing interventions for adrenal insufficiency using donor-specific reprogrammed Cells. Cell Rep, 22:1236–1249.
36.
SunB, LuoX, YangC, LiuP, YangY, DongX, YangZ, XuJ, ZhangY and LiL. (2019). Therapeutic effects of human urine-derived stem cells in a rat model of cisplatin-induced acute kidney injury in vivo and in vitro. Stem Cells Int, 2019:8035076.
37.
HuC, FangS, GongM, BiY and HeY. (2020). Comparison of biological characteristics of human urine-derived stem cells and human umbilical cord mesenchymal stem cells. Chin J Cell Bio, 42:239–247 (In Chinese).
38.
ZarshenasMM, FarrokhiRR, AkhaveinM and KiafarMR. (2016). A panoramic view of chronic liver diseases and natural remedies reported in Traditional Persian Medicine. Curr Pharm Des, 22:350–364.
39.
XieH, ZhaoJ, LianN, LinS, XieQ and ZhuoH. (2020). Clinical characteristics of non-ICU hospitalized patients with coronavirus disease 2019 and liver injury: a retrospective study. Liver Int, 40:1321–1326.
40.
ChenS, LiuH, LiT, HuangR, GuiR and ZhangJ. (2020). Correlation analysis of coagulation dysfunction and liver damage in patients with novel coronavirus pneumonia: a single-center, retrospective, observational study. Ups J Med Sci, 125:293–296.
41.
LeiM, LiK, LiB, GaoLN, ChenFM and JinY. (2014). Mesenchymal stem cell characteristics of dental pulp and periodontal ligament stem cells after in vivo transplantation. Biomaterials, 35:6332–6343.
42.
LiuT, WuC, WengG, ZhaoZ, HeX, FuC, SuiZ and HuangSX. (2017). Bufalin inhibits cellular proliferation and cancer stem cell-like phenotypes via upregulation of MiR-203 in glioma. Cell Physiol Biochem, 44:671–681.
43.
LataJ. (2012). Hepatorenal syndrome. World J Gastroenterol, 18:4978–4984.
44.
BezerraJA, WellsRG, MackCL, KarpenSJ, HoofnagleJH, DooE and SokolRJ. (2018). Biliary atresia: clinical and research challenges for the twenty-first century. Hepatology, 68:1163–1173.
45.
FukumotoK, FukuiT, KawaguchiK, NakamuraS, HakiriS, OzekiN, MoriS, GotoM, HashimotoK, TateyamaH and YokoiK. (2019). The tumor doubling time is a useful parameter for predicting the histological type of thymic epithelial tumors. Surg Today, 49:656–660.
46.
Cárdenas-LeónCG, Montoya-ContrerasA, Mäemets-AllasK, JaksV and Salazar-OlivoLA. (2020). A human preadipocyte cell strain with multipotent differentiation capability as an in vitro model for adipogenesis. In Vitro Cell Dev Biol Anim, 56:399–411.
47.
PinhoS and FrenettePS. (2019). Haematopoietic stem cell activity and interactions with the niche. Nat Rev Mol Cell Biol, 20:303–320.
48.
DekoninckS and BlanpainC. (2019). Stem cell dynamics, migration and plasticity during wound healing. Nat Cell Biol, 21:18–24.
49.
FuX, LiuG, HalimA, JuY, LuoQ and SongAG. (2019). Mesenchymal stem cell migration and tissue repair. Cells, 8:784.
50.
BharadwajS, LiuG, ShiY, WuR, YangB, HeT, FanY, LuX, ZhouX, et al. (2013). Multipotential differentiation of human urine-derived stem cells: potential for therapeutic applications in urology. Stem Cells, 31:1840–1856.
51.
ChenAJ, PiJK, HuJG, HuangYZ, GaoHW, LiSF, Li-LingJ and XieHQ. (2020). Identification and characterization of two morphologically distinct stem cell subpopulations from human urine samples. Sci China Life Sci, 63:712–723.
52.
LiuW, WangZ, HouJG, ZhouYD, HeYF, JiangS, WangYP, RenS and LiW. (2018). The liver protection effects of maltol, a flavoring agent, on carbon tetrachloride-induced acute liver injury in mice via inhibiting apoptosis and inflammatory response. Molecules, 23:2120.
53.
ForoutanT, AhmadiF, MoayerF and KhalvatiS. (2020). Effects of intraperitoneal injection of magnetic graphene oxide on the improvement of acute liver injury induced by CCl(4). Biomater Res, 24:14.
54.
XiaP, HeH, KristineMS, GuanW, GaoJ, WangZ, HuJ, HanL, LiJ, HanW and YuY. (2018). Therapeutic effects of recombinant human S100A6 and soluble receptor for advanced glycation end products(sRAGE) on CCl(4)-induced liver fibrosis in mice. Eur J Pharmacol, 833:86–93.
55.
TabetE, GenetV, TiahoF, Lucas-ClercC, Gelu-SimeonM, Piquet-PellorceC and SamsonM. (2016). Chlordecone potentiates hepatic fibrosis in chronic liver injury induced by carbon tetrachloride in mice. Toxicol Lett, 255:1–10.
56.
XiangX, FengD, HwangS, RenT, WangX, TrojnarE, MatyasC, MoR, ShangD, et al. (2020). Interleukin-22 ameliorates acute-on-chronic liver failure by reprogramming impaired regeneration pathways in mice. J Hepatol, 72:736–745.
57.
ShresthaN, ChandL, HanMK, LeeSO, KimCY and JeongYJ. (2016). Glutamine inhibits CCl4 induced liver fibrosis in mice and TGF-β1 mediated epithelial-mesenchymal transition in mouse hepatocytes. Food Chem Toxicol, 93:129–137.
58.
LiuD, LiuL, HuZ, SongZ, WangY and ChenZ. (2018). Evaluation of the oxidative stress-related genes ALOX5, ALOX5AP, GPX1, GPX3 and MPO for contribution to the risk of type 2 diabetes mellitus in the Han Chinese population. Diab Vasc Dis Res, 15:336–339.
59.
SouzaLB, MazieroC, LazzarinMC, QuintanaHT, ToméTC, BaptistaVIA and de OliveiraF. (2020). Presence of metalloproteinases 2 and 9 and 8-OHdG in the fibrotic process in skeletal muscle of Mdx mice. Acta Histochem, 122:151458.
60.
ZhangGZ, SunHC, ZhengLB, GuoJB and ZhangXL. (2017). In vivo hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells: therapeutic effect on liver fibrosis/cirrhosis. World J Gastroenterol, 23:8152–8168.
61.
MaHC, ShiXL, RenHZ, YuanXW and DingYT. (2014). Targeted migration of mesenchymal stem cells modified with CXCR4 to acute failing liver improves liver regeneration. World J Gastroenterol, 20:14884–14894.
62.
MilosavljevicN, GazdicM, Simovic MarkovicB, ArsenijevicA, NurkovicJ, DolicaninZ, DjonovV, LukicML and VolarevicV. (2017). Mesenchymal stem cells attenuate acute liver injury by altering ratio between interleukin 17 producing and regulatory natural killer T cells. Liver Transpl, 23:1040–1050.
63.
PerugorriaMJ, Esparza-BaquerA, OakleyF, LabianoI, KorosecA, JaisA, MannJ, TiniakosD, Santos-LasoA, et al. (2019). Non-parenchymal TREM-2 protects the liver from immune-mediated hepatocellular damage. Gut, 68:533–546.
64.
TasnimF, XingJ, HuangX, MoS, WeiX, TanMH and YuH. (2019). Generation of mature kupffer cells from human induced pluripotent stem cells. Biomaterials, 192:377–391.
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