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The Innovation Life > 2025 Vol. 3 > No. 3 > 100147
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Ovarian extracellular matrix hydrogel microspheres increase the efficacy of stem cell treatment in premature ovarian insufficiency

  • 1.

    Department of Obstetrics and Gynecology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases; Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology; Guangdong-Hong Kong-Macao Greater Bay Area Higher Education Joint Laboratory of Maternal-Fetal Medicine; The Third Affiliated Hospital, Guangzhou Medical University, Guangzhou 510150, China

  • 2.

    National Engineering Research Centre for Tissue Restoration and Reconstruction and Key Laboratory of Biomedical Engineering of Guangdong Province South China University of Technology Guangzhou 510640, China

  • 3.

    Key Laboratory of Biomedical Engineering of Guangdong Province, South China University of Technology, Guangzhou 510006, China

  • 4.

    The First Affiliated Hospital of Shenzhen University, Reproductive Medicine Centre, Shenzhen Second People’s Hospital, Shenzhen 518035, China

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The Innovation Life  3(3),  https://doi.org/10.59717/j.xinn-life.2025.100147  |  Cite this article
    GRAPHICAL ABSTRACT
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    1. Ovarian-ECM hydrogel microspheres serve as an effective carrier for BMSCs delivery.

      OG-HMPs enhance BMSCs proliferation and paracrine effects in vitro.

      OG-HMPs prolong BMSCs retention time in ovaries.

      OG-HMPs@BMSCs restore estrous cycles and reproductive outcomes in POI mice.

    • ABSTRACT
  • Premature ovarian insufficiency (POI) affects approximately 1-2% of reproductive-aged women, significantly impacting their reproductive potential and systemic health. Stem cell-based therapy has demonstrated promising therapeutic efficacy in restoring ovarian function through promoting neovascularization, attenuating fibrosis, and suppressing ovarian cell apoptosis. However, conventional cell transplantation approaches are limited by poor cell viability and retention. Here, we developed a novel therapeutic strategy utilizing hydrogel microspheres (OG-HMPs) fabricated from decellularized ovarian extracellular matrix (OECM) and gelatin as delivery vehicles for bone marrow mesenchymal stem cells (BMSCs) to treat POI. OG-HMPs effectively supported BMSCs attachment and proliferation, facilitating the formation of high-density cellular spheroids. The retained ovary-specific bioactive components in OECM recapitulate the native ovarian microenvironment, enhancing cell survival and significantly elevating the expression of angiogenic factors including VEGF and HGF. Moreover, OG-HMPs@BMSCs demonstrate immunomodulatory effects on activated macrophages and cytoprotective properties against chemically-induced granulosa cell apoptosis. In vivo studies using POI mouse models confirmed that OG-HMPs@BMSCs transplantation significantly enhanced BMSCs retention within ovarian tissue and improved both endocrine function, estrous cycle pattern, and reproductive outcomes compared to conventional cell delivery. Collectively, OG-HMPs, exhibiting excellent biocompatibility and biological activity, represent a promising therapeutic platform for POI treatment through enhanced stem cell-mediated tissue regeneration.
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  • [1] De Vos M., Devroey P. and Fauser B.C. (2010). Primary ovarian insufficiency. Lancet 376:911−921. DOI:10.1016/S0140-6736(10)60355-8

    View in Article CrossRef Google Scholar

    [2] Falsetti L., Scalchi S., Villani M.T., et al. (1999). Premature ovarian failure. Gynecol. Endocrinol. 13:189−195. DOI:10.3109/09513599909167554

    View in Article CrossRef Google Scholar

    [3] Cao C., Pei W., Zhou P., et al., (2024). GNAS deficiency is associated with premature ovarian insufficiency phenotype via regulating ovarian steroidogenesis. The Innovation Life 2: 100080. DOI:10.59717/j.xinn-life.2024.100080

    View in Article Google Scholar

    [4] Chernyshov V.P., Radysh T.V., Gura I.V., et al. (2001). Immune Disorders in Women with Premature Ovarian Failure in Initial Period. Am. J. Reprod. Immunol. 46:220−5. DOI:10.1034/j.1600-0897.2001.d01-5.x

    View in Article CrossRef Google Scholar

    [5] Deng T., He J., Yao Q., et al. (2021). Human Umbilical Cord Mesenchymal Stem Cells Improve Ovarian Function in Chemotherapy-Induced Premature Ovarian Failure Mice Through Inhibiting Apoptosis and Inflammation via a Paracrine Mechanism. Reprod. Sci. 28:1718−32. DOI:10.1007/s43032-021-00499-1

    View in Article CrossRef Google Scholar

    [6] Kapoor E. (2023). Premature Ovarian Insufficiency. Curr. Opin. Endocr. Metab. Res. 28:100435. DOI:10.1016/j.coemr.2023.100435

    View in Article CrossRef Google Scholar

    [7] Zhang S., Zhu D., Li Z., et al. (2021). A stem cell-derived ovarian regenerative patch restores ovarian function and rescues fertility in rats with primary ovarian insufficiency. Theranostics 11:8894−908. DOI:10.7150/thno.61690

    View in Article CrossRef Google Scholar

    [8] Takahashi A., Yousif A., Hong L., et al. (2021). Premature ovarian insufficiency: pathogenesis and therapeutic potential of mesenchymal stem cell. J. Mol. Med. 99:637−50. DOI:10.1007/s00109-021-02055-5

    View in Article CrossRef Google Scholar

    [9] Na J. and Kim G.J. (2020). Recent trends in stem cell therapy for premature ovarian insufficiency and its therapeutic potential: a review. J. Ovarian Res. 13:74. DOI:10.1186/s13048-020-00671-2

    View in Article CrossRef Google Scholar

    [10] Wang J., Liu W., Yu D., et al. (2021). Research Progress on the Treatment of Premature Ovarian Failure Using Mesenchymal Stem Cells: A Literature Review. Front. Cell Dev. Biol. 9:749822. DOI:10.3389/fcell.2021.749822

    View in Article CrossRef Google Scholar

    [11] Sun B., Ma Y., Wang F., et al. (2019). miR-644-5p carried by bone mesenchymal stem cell-derived exosomes targets regulation of p53 to inhibit ovarian granulosa cell apoptosis. Stem Cell Res. Ther. 10:360. DOI:10.1186/s13287-019-1442-3

    View in Article CrossRef Google Scholar

    [12] Ran X., Wang Q., Sun Y., et al. (2024). Dual microparticles programmed delivery system regulating stem cell-based cartilage regeneration by cartilage-specific matrix hydrogels. Compos. Part B: Eng. 272:111221. DOI:10.1016/j.compositesb.2024.111221

    View in Article CrossRef Google Scholar

    [13] Fu X., He Y., Xie C., et al. (2008). Bone marrow mesenchymal stem cell transplantation improves ovarian function and structure in rats with chemotherapy-induced ovarian damage. Cytotherapy 10:353−363. DOI:10.1080/14653240802035926

    View in Article CrossRef Google Scholar

    [14] N K., Hr S., M M., et al. (2018). Effect of transplantation of bone marrow stromal cell-conditioned medium on ovarian function, morphology and cell death in cyclophosphamide-treated rats. Cell J. 20:10−18. DOI:10.22074/cellj.2018.4919

    View in Article CrossRef Google Scholar

    [15] Fischer U.M., Harting M.T., Jimenez F., et al. (2009). Pulmonary passage is a major obstacle for intravenous stem cell delivery: the pulmonary first-pass effect. Stem Cells Dev. 18:683−691. DOI:10.1089/scd.2008.0253

    View in Article CrossRef Google Scholar

    [16] Wang L., Mei Q., Xie Q., et al. (2022). A comparative study of mesenchymal stem cells transplantation approach to antagonize age-associated ovarian hypofunction with consideration of safety and efficiency. J. Adv. Res. 38:245−259. DOI:10.1016/j.jare.2021.09.001

    View in Article CrossRef Google Scholar

    [17] Laronda M.M., Rutz A.L., Xiao S., et al. (2017). A bioprosthetic ovary created using 3D printed microporous scaffolds restores ovarian function in sterilized mice. Nat. Commun. 8:1−10. DOI:10.1038/ncomms15261

    View in Article CrossRef Google Scholar

    [18] Taraballi F., Sushnitha M., Tsao C., et al. (2018). Biomimetic tissue engineering: tuning the immune and inflammatory response to implantable biomaterials. Adv. Healthc. Mater. 7:1800490. DOI:10.1002/adhm.201800490

    View in Article CrossRef Google Scholar

    [19] Que R., Mohraz A., Da Silva N.A., et al. (2014). Expanding functionality of recombinant human collagen through engineered non-native cysteines. Biomacromolecules 15:3540−3549. DOI:10.1021/bm500735d

    View in Article CrossRef Google Scholar

    [20] Chen Y., Chen L.-F., Wang Y., et al. (2025). Engineered dECM-based microsystem promotes cartilage regeneration in osteoarthritis by synergistically enhancing chondrogenesis of BMSCs and anti-inflammatory effect. Compos. Part B: Eng. 290:111974. DOI:10.1016/j.compositesb.2024.111974

    View in Article CrossRef Google Scholar

    [21] Yuan X., Wei Y., Villasante A., et al. (2017). Stem cell delivery in tissue-specific hydrogel enabled meniscal repair in an orthotopic rat model. Biomaterials 132:59−71. DOI:10.1016/j.biomaterials.2017.04.004

    View in Article CrossRef Google Scholar

    [22] Rao N., Agmon G., Tierney M.T., et al. (2017). Engineering an injectable muscle-specific microenvironment for improved cell delivery using a nanofibrous extracellular matrix hydrogel. ACS Nano 11:3851−3859. DOI:10.1021/acsnano.7b00093

    View in Article CrossRef Google Scholar

    [23] Wu T., Huang K.-C., Yan J.-F., et al. (2023). Extracellular matrix-derived scaffolds in constructing artificial ovaries for ovarian failure: a systematic methodological review. Hum. Reprod. Open 2023:hoad014. DOI:10.1093/hropen/hoad014

    View in Article CrossRef Google Scholar

    [24] Zhao Z., Wang Z., Li G., et al. (2021). Injectable microfluidic hydrogel microspheres for cell and drug delivery. Adv. Funct. Mater. 2103339:1−24. DOI:10.1002/adfm.202103339

    View in Article CrossRef Google Scholar

    [25] Wang S., Wang Z., Shen Z., et al. (2024). Magnetic soft microrobots for erectile dysfunction therapy. Proc. Natl. Acad. Sci. USA 121:e2407809121. DOI:10.1073/pnas.2407809121

    View in Article CrossRef Google Scholar

    [26] An G., Guo F., Liu X., et al. (2020). Functional reconstruction of injured corpus cavernosa using 3D-printed hydrogel scaffolds seeded with HIF-1α-expressing stem cells. Nat. Commun. 11:2687. DOI:10.1038/s41467-020-16192-x

    View in Article CrossRef Google Scholar

    [27] Francés-Herrero E., Lopez R., Campo H., et al. (2023). Advances of xenogeneic ovarian extracellular matrix hydrogels for in vitro follicle development and oocyte maturation. Biomater. Adv. 151:213480. DOI:10.1016/j.bioadv.2023.213480

    View in Article CrossRef Google Scholar

    [28] Li Y., Zhang H., Cai C., et al. (2024). Microfluidic encapsulation of exosomes derived from lipopolysaccharide-treated mesenchymal stem cells in hyaluronic acid methacryloyl to restore ovarian function in mice. Adv. Healthc. Mater. 13:2303068. DOI:10.1002/adhm.202303068

    View in Article CrossRef Google Scholar

    [29] Liu X., Chen Y., Mao A.S., et al. (2020). Molecular recognition-directed site-specific release of stem cell differentiation inducers for enhanced joint repair. Biomaterials 232:119644. DOI:10.1016/j.biomaterials.2019.119644

    View in Article CrossRef Google Scholar

    [30] Wang Z., An G., Zhu Y., et al. (2019). 3D-printable self-healing and mechanically reinforced hydrogels with host-guest non-covalent interactions integrated into covalently linked networks. Mater. Horiz. 6:733−742. DOI:10.1039/c8mh01208c

    View in Article CrossRef Google Scholar

    [31] Zhang W., Chen J., Tao J., et al. (2013). The use of type 1 collagen scaffold containing stromal cell-derived factor-1 to create a matrix environment conducive to partial-thickness cartilage defects repair. Biomaterials 34:713−723. DOI:10.1016/j.biomaterials.2012.10.027

    View in Article CrossRef Google Scholar

    [32] Kulus J., Kulus M., Kranc W., et al. (2021). Transcriptomic profile of new gene markers encoding proteins responsible for structure of porcine ovarian granulosa cells. Biology (Basel) 10:1214. DOI:10.3390/biology10111214

    View in Article CrossRef Google Scholar

    [33] Mantri M., Zhang H.H., Spanos E., et al. (2024). A spatiotemporal molecular atlas of the ovulating mouse ovary. Proc. Natl. Acad. Sci. USA 121:e2317418121. DOI:10.1073/pnas.2317418121

    View in Article CrossRef Google Scholar

    [34] Crapo P.M., Gilbert T.W., Badylak S.F. (2011). An overview of tissue and whole organ decellularization processes. Biomaterials 32:3233−3243. DOI:10.1016/j.biomaterials.2011.01.057

    View in Article CrossRef Google Scholar

    [35] Kennelly H., Mahon B.P., English K. (2016). Human mesenchymal stromal cells exert HGF dependent cytoprotective effects in a human relevant pre-clinical model of COPD. Sci. Rep. 6:38207. DOI:10.1038/srep38207

    View in Article CrossRef Google Scholar

    [36] Chang H.-K., Kim P.-H., Kim D.W., et al. (2018). Coronary stents with inducible VEGF/HGF-secreting UCB-MSCs reduced restenosis and increased re-endothelialization in a swine model. Exp. Mol. Med. 50:1−14. DOI:10.1038/s12276-018-0143-9

    View in Article CrossRef Google Scholar

    [37] Chi A., Yang B., Dai H., et al. (2024). Stem Leydig cells support macrophage immunological homeostasis through mitochondrial transfer in mice. Nat. Commun. 15:2120. DOI:10.1038/s41467-024-46190-2

    View in Article CrossRef Google Scholar

    [38] Saraiva M. and O’Garra A. (2010). The regulation of IL-10 production by immune cells. Nat. Rev. Immunol. 10:170−181. DOI:10.1038/nri2711

    View in Article CrossRef Google Scholar

    [39] Huang Y., Zhu M., Liu Z., et al. (2022). Bone marrow mesenchymal stem cells in premature ovarian failure: mechanisms and prospects. Front. Immunol. 13:997808. DOI:10.3389/fimmu.2022.997808

    View in Article CrossRef Google Scholar

    [40] Ding C., Zou Q., Wang F., et al. (2018). Human amniotic mesenchymal stem cells improve ovarian function in natural aging through secreting hepatocyte growth factor and epidermal growth factor. Stem Cell Res. Ther. 9:55. DOI:10.1186/s13287-018-0781-9

    View in Article CrossRef Google Scholar

    [41] Zhou Y., Zhou J., Xu X., et al. (2021). Matrigel/umbilical cord-derived mesenchymal stem cells promote granulosa cell proliferation and ovarian vascularization in a mouse model of premature ovarian failure. Stem Cells Dev. 30:782−796. DOI:10.1089/scd.2021.0005

    View in Article CrossRef Google Scholar

    [42] Ma M., Wang H., Zhang Y., et al. (2021). circRNA-mediated inhibin–activin balance regulation in ovarian granulosa cell apoptosis and follicular atresia. Int. J. Mol. Sci. 22:9113. DOI:10.3390/ijms22179113

    View in Article CrossRef Google Scholar

    [43] Chiti M.-C., Vanacker J., Ouni E., et al. (2022). Ovarian extracellular matrix-based hydrogel for human ovarian follicle survival in vivo: a pilot work. J. Biomed. Mater. Res. B 110:1012−1022. DOI:10.1002/jbm.b.34974

    View in Article CrossRef Google Scholar

    [44] Yi X., Liu F., Gao K., et al. (2022). Reconstructable uterus‐derived materials for uterus recovery toward efficient live births. Adv. Mater. 34:2106510. DOI:10.1002/adma.202106510

    View in Article CrossRef Google Scholar

    [45] Chiti M.-C., Vanacker J., Ouni E., et al. (2022). Ovarian extracellular matrix‐based hydrogel for human ovarian follicle survival in vivo: a pilot work. J. Biomed. Mater. Res. B 110:1012−1022. DOI:10.1002/jbm.b.34974

    View in Article CrossRef Google Scholar

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  • Cite this article:

    Liu X., Chen M., Liang X., et al. (2025). Ovarian extracellular matrix hydrogel microspheres increase the efficacy of stem cell treatment in premature ovarian insufficiency. The Innovation Life 3:100147. https://doi.org/10.59717/j.xinn-life.2025.100147
    Liu X., Chen M., Liang X., et al. (2025). Ovarian extracellular matrix hydrogel microspheres increase the efficacy of stem cell treatment in premature ovarian insufficiency. The Innovation Life 3:100147. https://doi.org/10.59717/j.xinn-life.2025.100147

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