Effect and mechanism of transplantation of human umbilical cord mesenchymal stem cells with overexpression of the Numb gene in treatment of cholestatic liver fibrosis

Shihao ZHANG; Changqing ZHAO; Mingyan YANG; Feifei XING; Wei LIU; Gaofeng CHEN; Jiamei CHEN; Ping LIU; Yongping MU

doi:10.12449/JCH260110

Volume 42 Issue 1

Jan. 2026

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Effect and mechanism of transplantation of human umbilical cord mesenchymal stem cells with overexpression of the Numb gene in treatment of cholestatic liver fibrosis

DOI: 10.12449/JCH260110

1.
Institute of Liver Diseases，Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine，Shanghai 201203，China
2.
Department of Hepatology，Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine，Shanghai 201203，China

Research funding:

General Project of National Natural Science Foundation of China (82574932);

General Project of National Natural Science Foundation of China (81874390);

Special Project for Biomedical Science and Technology Support of the “Science and Technology Innovation Action Plan” of Shanghai Science and Technology Commission in 2022 (22S11901700);

Shanghai Natural Science Foundation (21ZR1464100);

Shanghai Key Specialty of Traditional Chinese Clinical Medicine (shslczdzk01201)

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Corresponding author: MU Yongping， ypmu8888@126.com （ORCID： 0000-0002-6808-8243）
Received Date: 2025-07-18
Accepted Date: 2025-10-31
Published Date: 2026-01-25

Abstract

Abstract

Objective To investigate the effect and mechanism of transplantation of human umbilical cord mesenchymal stem cell （hUC-MSC） with overexpression of the Numb gene in the treatment of cholestatic liver fibrosis （CLF）. Methods The technique of lentiviral transfection was used to induce the overexpression of the Numb gene in hUC-MSC （hUC-MSC^Numb-OE）， and hUC-MSC transfected with empty vector （hUC-MSC^OE-EV） was used as negative control. Bile duct ligation （BDL） was performed to establish a rat model of CLF， and then the rats were randomly divided into BDL group， hUC-MSC group， hUC-MSC^OE-EV group， and hUC-MSC^Numb-OEgroup， while a sham-operation group was also established. The rats in the intervention groups were given a single splenic injection of the corresponding cells after BDL， and samples were collected at the end of week 4. Related indicators were measured， including serum biochemistry， liver histopathology， the content of hydroxyproline （Hyp） in the liver， hepatic stellate cell activation， ductular reaction， liver regeneration， and the expression levels of key molecules in the Numb-p53 signaling axis. A one-way analysis of variance was used for comparison of continuous data between multiple groups， and the least significant difference t-test was used for further comparison between two groups. Results Compared with the BDL group， the hUC-MSC group and the hUC-MSC^OE-EV group had significant reductions in the levels of serum biochemical parameters （aspartate aminotransferase， gamma-glutamyl transpeptidase， total bile acid， total bilirubin， and direct bilirubin）， liver fibrosis markers （the content of Hyp and the expression levels of alpha-smooth muscle actin， tumor necrosis factor-α， and transforming growth factor-beta 1）， and ductular reaction markers （the expression levels of CK7 and CK19）（all P <0.05）， and compared with the hUC-MSC^OE-EV group， the hUC-MSC^Numb-OE group had significantly greater improvements in the above indicators （all P <0.05）. In addition， compared with the hUC-MSC^OE-EV group， the hUC-MSC^Numb-OE group had significant improvements in the expression levels of liver regeneration-related markers （albumin and hepatocyte nuclear factor 4α） and the molecules associated with the Numb-p53 signaling axis （Numb， pNumb， Mdm2， and p53）（all P <0.05）. Conclusion Overexpression of the Numb gene can enhance the therapeutic effect of hUC-MSC on CLF， possibly by activating the Numb-PTB^L-p53-HNF4α axis， promoting the hepatic differentiation of hUC-MSCs and subsequently enhancing liver regeneration.
- Hepatic Fibrosis,
- Numb Gene,
- Umbilical Cord Mesenchymal Stem Cell,
- Ductular Reaction,
- Numb-PTB^L-p53-HNF4α axis

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References

[1]	KISSELEVA T, BRENNER D. Molecular and cellular mechanisms of liver fibrosis and its regression[J]. Nat Rev Gastroenterol Hepatol, 2021, 18( 3): 151- 166. DOI: 10.1038/s41575-020-00372-7.
[2]	FABRIS L, FIOROTTO R, SPIRLI C, et al. Pathobiology of inherited biliary diseases: A roadmap to understand acquired liver diseases[J]. Nat Rev Gastroenterol Hepatol, 2019, 16( 8): 497- 511. DOI: 10.1038/s41575-019-0156-4.
[3]	CORPECHOT C, CARRAT F, BONNAND AM, et al. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis[J]. Hepatology, 2000, 32( 6): 1196- 1199. DOI: 10.1053/jhep.2000.20240.
[4]	LIANG J, ZHANG HY, ZHAO C, et al. Effects of allogeneic mesenchymal stem cell transplantation in the treatment of liver cirrhosis caused by autoimmune diseases[J]. Int J Rheum Dis, 2017, 20( 9): 1219- 1226. DOI: 10.1111/1756-185X.13015.
[5]	CHEN Z, KUANG QT, LAO XJ, et al. Differentiation of UC-MSCs into hepatocyte-like cells in partially hepatectomized model rats[J]. Exp Ther Med, 2016, 12( 3): 1775- 1779. DOI: 10.3892/etm.2016.3543.
[6]	DRISCOLL J, PATEL T. The mesenchymal stem cell secretome as an acellular regenerative therapy for liver disease[J]. J Gastroenterol, 2019, 54( 9): 763- 773. DOI: 10.1007/s00535-019-01599-1.
[7]	LIU PY, MAO YC, XIE Y, et al. Stem cells for treatment of liver fibrosis/cirrhosis: Clinical progress and therapeutic potential[J]. Stem Cell Res Ther, 2022, 13( 1): 356. DOI: 10.1186/s13287-022-03041-5.
[8]	COUTURIER L, VODOVAR N, SCHWEISGUTH F. Endocytosis by Numb breaks Notch symmetry at cytokinesis[J]. Nat Cell Biol, 2012, 14( 2): 131- 139. DOI: 10.1038/ncb2419.
[9]	SIDDIQUE HR, FELDMAN DE, CHEN CL, et al. NUMB phosphorylation destabilizes p53 and promotes self-renewal of tumor-initiating cells by a NANOG-dependent mechanism in liver cancer[J]. Hepatology, 2015, 62( 5): 1466- 1479. DOI: 10.1002/hep.27987.
[10]	COLALUCA IN, TOSONI D, NUCIFORO P, et al. NUMB controls p53 tumour suppressor activity[J]. Nature, 2008, 451( 7174): 76- 80. DOI: 10.1038/nature06412.
[11]	FILIPPONE MG, FREDDI S, ZECCHINI S, et al. Aberrant phosphorylation inactivates Numb in breast cancer causing expansion of the stem cell pool[J]. J Cell Biol, 2022, 221( 12): e202112001. DOI: 10.1083/jcb.202112001.
[12]	BALOGHOVA N, LIDAK T, CERMAK L. Ubiquitin ligases involved in the regulation of Wnt, TGF-β, and notch signaling pathways and their roles in mouse development and homeostasis[J]. Genes(Basel), 2019, 10( 10): 815. DOI: 10.3390/genes10100815.
[13]	ESPANOLA SG, SONG H, RYU E, et al. Haematopoietic stem cell-dependent Notch transcription is mediated by p53 through the Histone chaperone Supt16h[J]. Nat Cell Biol, 2020, 22( 12): 1411- 1422. DOI: 10.1038/s41556-020-00604-7.
[14]	XU YN, XU W, ZHANG X, et al. BM-MSCs overexpressing the Numb enhance the therapeutic effect on cholestatic liver fibrosis by inhibiting the ductular reaction[J]. Stem Cell Res Ther, 2023, 14( 1): 45. DOI: 10.1186/s13287-023-03276-w.
[15]	ZHANG X, DU GL, XU Y, et al. Inhibition of Notch signaling pathway prevents cholestatic liver fibrosis by decreasing the differentiation of hepatic progenitor cells into cholangiocytes[J]. Lab Invest, 2016, 96( 3): 350- 360. DOI: 10.1038/labinvest.2015.149.
[16]	SHU YK, XU Q, XU YH, et al. Loss of Numb promotes hepatic progenitor expansion and intrahepatic cholangiocarcinoma by enhancing Notch signaling[J]. Cell Death Dis, 2021, 12( 11): 966. DOI: 10.1038/s41419-021-04263-w.
[17]	YU YB, SONG Y, CHEN Y, et al. Differentiation of umbilical cord mesenchymal stem cells into hepatocytes in comparison with bone marrow mesenchymal stem cells[J]. Mol Med Rep, 2018, 18( 2): 2009- 2016. DOI: 10.3892/mmr.2018.9181.
[18]	SUK KT, YOON JH, KIM MY, et al. Transplantation with autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: Phase 2 trial[J]. Hepatology, 2016, 64( 6): 2185- 2197. DOI: 10.1002/hep.28693.
[19]	SHI M, LI YY, XU RN, et al. Mesenchymal stem cell therapy in decompensated liver cirrhosis: A long-term follow-up analysis of the randomized controlled clinical trial[J]. Hepatol Int, 2021, 15( 6): 1431- 1441. DOI: 10.1007/s12072-021-10199-2.
[20]	MOHAMADNEJAD M, ALIMOGHADDAM K, BAGHERI M, et al. Randomized placebo-controlled trial of mesenchymal stem cell transplantation in decompensated cirrhosis[J]. Liver Int, 2013, 33( 10): 1490- 1496. DOI: 10.1111/liv.12228.
[21]	LANTHIER N, LIN-MARQ N, RUBBIA-BRANDT L, et al. Autologous bone marrow-derived cell transplantation in decompensated alcoholic liver disease: What is the impact on liver histology and gene expression patterns[J]. Stem Cell Res Ther, 2017, 8( 1): 88. DOI: 10.1186/s13287-017-0541-2.
[22]	WEI HY, LI FF, XUE TT, et al. microRNA-122-functionalized DNA tetrahedron stimulate hepatic differentiation of human mesenchymal stem cells for acute liver failure therapy[J]. Bioact Mater, 2023, 28: 50- 60. DOI: 10.1016/j.bioactmat.2023.04.024.
[23]	XU T, NI MM, XING-LI, et al. NLRC5 regulates TGF-β1-induced proliferation and activation of hepatic stellate cells during hepatic fibrosis[J]. Int J Biochem Cell Biol, 2016, 70: 92- 104. DOI: 10.1016/j.biocel.2015.11.010.
[24]	ZHANG K, ZHANG MX, MENG XX, et al. Targeting GPR65 alleviates hepatic inflammation and fibrosis by suppressing the JNK and NF-κB pathways[J]. Mil Med Res, 2023, 10( 1): 56. DOI: 10.1186/s40779-023-00494-4.
[25]	CHOI SS, DIEHL AM. Epithelial-to-mesenchymal transitions in the liver[J]. Hepatology, 2009, 50( 6): 2007- 2013. DOI: 10.1002/hep.23196.
[26]	NOVO E, di BONZO LV, CANNITO S, et al. Hepatic myofibroblasts: A heterogeneous population of multifunctional cells in liver fibrogenesis[J]. Int J Biochem Cell Biol, 2009, 41( 11): 2089- 2093. DOI: 10.1016/j.biocel.2009.03.010.
[27]	GUNEWARDENA S, HUCK I, WALESKY C, et al. Progressive loss of hepatocyte nuclear factor 4 alpha activity in chronic liver diseases in humans[J]. Hepatology, 2022, 76( 2): 372- 386. DOI: 10.1002/hep.32326.
[28]	XU YY, ZHU YD, HU SW, et al. Hepatocyte nuclear factor 4α prevents the steatosis-to-NASH progression by regulating p53 and bile acid signaling(in mice)[J]. Hepatology, 2021, 73( 6): 2251- 2265. DOI: 10.1002/hep.31604.
[29]	COLALUCA IN, BASILE A, FREIBURGER L, et al. A Numb-Mdm2 fuzzy complex reveals an isoform-specific involvement of Numb in breast cancer[J]. J Cell Biol, 2018, 217( 2): 745- 762. DOI: 10.1083/jcb.201709092.
[30]	SU DX, LI YX, ZHANG WJ, et al. SPTAN1/NUMB axis senses cell density to restrain cell growth and oncogenesis through Hippo signaling[J]. J Clin Invest, 2023, 133( 20): e168888. DOI: 10.1172/JCI168888.

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Effect and mechanism of transplantation of human umbilical cord mesenchymal stem cells with overexpression of the Numb gene in treatment of cholestatic liver fibrosis

DOI: 10.12449/JCH260110

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