Journal of Zhejiang University SCIENCE  B

Accepted manuscript available online (unedited version)


Influence of pathological microenvironments on mesenchymal stem/stromal cell fate: role of long non-coding RNAs in bone-related diseases


Author(s):  Jingbo LAI

Affiliation(s):  College of Life Sciences, and Department of Genetic and Metabolic Disease, Children’s Hospital Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Zhejiang University, Hangzhou 310058, China; more

Corresponding email(s): 

Key Words:  Mesenchymal stem/stromal cell (MSC), Long non-coding RNA (lncRNA), Microenvironment, Cell differentiation, Bone disease


Jingbo LAI. Influence of pathological microenvironments on mesenchymal stem/stromal cell fate: role of long non-coding RNAs in bone-related diseases[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2500699

@article{title="Influence of pathological microenvironments on mesenchymal stem/stromal cell fate: role of long non-coding RNAs in bone-related diseases",
author="Jingbo LAI",
journal="Journal of Zhejiang University Science B",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2500699"
}

%0 Journal Article
%T Influence of pathological microenvironments on mesenchymal stem/stromal cell fate: role of long non-coding RNAs in bone-related diseases
%A Jingbo LAI
%J Journal of Zhejiang University SCIENCE B
%P 1080-1095
%@ 1673-1581
%D in press
%I Zhejiang University Press & Springer
doi="https://doi.org/10.1631/jzus.B2500699"

TY - JOUR
T1 - Influence of pathological microenvironments on mesenchymal stem/stromal cell fate: role of long non-coding RNAs in bone-related diseases
A1 - Jingbo LAI
J0 - Journal of Zhejiang University Science B
SP - 1080
EP - 1095
%@ 1673-1581
Y1 - in press
PB - Zhejiang University Press & Springer
ER -
doi="https://doi.org/10.1631/jzus.B2500699"


Abstract: 
The bidirectional relationship between pathological microenvironments and mesenchymal stem/stromal cells (MSCs) is known as a pivotal factor influencing the progression of bone-related disease and therapeutic outcomes. MSCs, characterized by their remarkable plasticity and excellent immunomodulatory abilities, play central roles in various physiological and pathological processes, especially in bone regeneration and repair. Under pathological conditions, such as osteoarthritis, osteoporosis, or bone tumors, the tissue microenvironment can significantly alter MSC behavior, leading to impaired differentiation, dysregulated immune responses, or abnormal tissue remodeling. This dynamic relationship is regulated by diverse molecular signals, where long non-coding RNAs (lncRNAs) emerge as critical regulators of MSC biology. LncRNAs influence MSC differentiation, immunomodulatory functions, and responses to microenvironmental cues through diverse molecular mechanisms. The systematic review elucidates the roles of various lncRNAs involved in different aspects of MSC biology under pathological conditions and their potential as therapeutic targets or biomarkers for bone-related disorders.

病理微环境对间充质干细胞/基质细胞命运的影响: 长链非编码RNA在骨相关疾病中的作用

赖靖博1,2, 潘若浪3, 郑静1, 陈烨1,2
1浙江大学生命科学学院, 浙江大学医学院附属儿童医院遗传与代谢科, 国家儿童健康与疾病临床医学研究中心, 中国杭州, 310058
2浙江省细胞与分子智能设计与开发重点实验室, 中国杭州, 310058
3浙江省细胞药物与应用技术研究重点实验室, 浙江省细胞药物和制品重点企业研究院, 中国杭州, 310018
摘要:病理微环境与间充质干细胞/基质细胞(MSC)间的双向关系是影响骨相关疾病进展以及治疗效果的关键因素。MSC因具有显著的可塑性和出色的免疫调节能力,在各种生理和病理过程中,尤其是在骨骼再生和修复中发挥着核心作用。在骨关节炎、骨质疏松或骨肿瘤等病理条件下,组织微环境可显著改变MSC的行为,导致其分化受损、免疫反应失调或组织重塑异常。上述动态关系由多种信号分子调控,其中长链非编码RNA(lncRNA)已成为MSC生物学功能的重要调节因子。LncRNA可通过多种分子机制影响MSC的分化、免疫调节功能及其对微环境信号的响应。本综述系统阐述了在病理条件下,多种lncRNA对MSC命运的调控,并探讨了其作为骨相关疾病治疗靶点或生物标志物的潜力。

关键词组:间充质干细胞/基质细胞(MSC);长链非编码RNA(lncRNA);微环境;细胞分化;骨疾病

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]SHA Al-Sammarraie, Ayaz-Güner Ş, Acar MB, et al., 2024. Mesenchymal stem cells from adipose tissue prone to lose their stemness associated markers in obesity related stress conditions. Sci Rep, 14:19702.

[2]Avnet S, di Pompo G, Lemma S, et al., 2019. Cause and effect of microenvironmental acidosis on bone metastases. Cancer Metastasis Rev, 38(1-2):133-147.

[3]Bernardo ME, Fibbe WE, 2013. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell, 13(4):392-402.

[4]Carlevaro-Fita J, Johnson R, 2019. Global positioning system: understanding long noncoding RNAs through subcellular localization. Mol Cell, 73(5):869-883.

[5]Cen SZ, Cai MX, Wang YH, et al., 2022. Aberrant lncRNA–mRNA expression profile and function networks during the adipogenesis of mesenchymal stem cells from patients with ankylosing spondylitis. Front Genet, 13:991875.

[6]Cheng A, Choi D, Lora M, et al., 2020. Human multipotent mesenchymal stromal cells cytokine priming promotes RAB27B-regulated secretion of small extracellular vesicles with immunomodulatory cargo. Stem Cell Res Ther, 11:539.

[7]Coan M, Haefliger S, Ounzain S, et al., 2024. Targeting and engineering long non-coding RNAs for cancer therapy. Nat Rev Genet, 25(8):578-595.

[8]Cortini M, Avnet S, Baldini N, 2017. Mesenchymal stroma: role in osteosarcoma progression. Cancer Lett, 405:90-99.

[9]Dong R, Bai Y, Dai JJ, et al., 2020. Engineered scaffolds based on mesenchymal stem cells/preosteoclasts extracellular matrix promote bone regeneration. J Tissue Eng, 11:2041731420926918.

[10]Fang TS, Zhou XH, Jin MC, et al., 2021. Molecular mechanisms of mechanical load-induced osteoarthritis. Int Orthop, 45(5):1125-1136.

[11]Feng J, Wang JX, Li CH, 2019. LncRNA GAS5 overexpression alleviates the development of osteoporosis through promoting osteogenic differentiation of MSCs via targeting microRNA-498 to regulate RUNX2. Eur Rev Med Pharmacol Sci, 23(18):7757-7765.

[12]Feng XD, Zhou JH, Chen JY, et al., 2022. Long non-coding RNA SNHG16 promotes human placenta-derived mesenchymal stem cell proliferation capacity through the PI3K/AKT pathway under hypoxia. World J Stem Cells, 14(9):714-728.

[13]Ferrer J, Dimitrova N, 2024. Transcription regulation by long non-coding RNAs: mechanisms and disease relevance. Nat Rev Mol Cell Biol, 25(5):396-415.

[14]Fu Y, Hu XY, Gao YY, et al., 2021. LncRNA ROR/miR-145-5p axis modulates the osteoblasts proliferation and apoptosis in osteoporosis. Bioengineered, 12(1):7714-7723.

[15]Garrido-Pascual P, Alonso-Varona A, Castro B, et al., 2020. H2O2-preconditioned human adipose-derived stem cells (HC016) increase their resistance to oxidative stress by overexpressing Nrf2 and bioenergetic adaptation. Stem Cell Res Ther, 11:335.

[16]Gu HJ, Huang ZY, Zhou KF, et al., 2021. Expression profile analysis of long non-coding RNA in OVX models-derived BMSCs for postmenopausal osteoporosis by RNA sequencing and bioinformatics. Front Cell Dev Biol, 9:719851.

[17]Guillamat-Prats R, 2021. The role of MSC in wound healing, scarring and regeneration. Cells, 10(7):1729.

[18]Guo QL, Zhai QM, Ji P, 2024. The role of mitochondrial homeostasis in mesenchymal stem cell therapy—potential implications in the treatment of osteogenesis imperfecta. Pharmaceuticals (Basel), 17(10):1297.

[19]He SW, Yang S, Zhang YR, et al., 2019. LncRNA ODIR1 inhibits osteogenic differentiation of hUC-MSCs through the FBXO25/H2BK120ub/H3K4me3/OSX axis. Cell Death Discov, 10(12):947.

[20]Hoshiba T, Kawazoe N, Chen GP, 2012. The balance of osteogenic and adipogenic differentiation in human mesenchymal stem cells by matrices that mimic stepwise tissue development. Biomaterials, 33(7):2025-2031.

[21]Hu W, Fei TY, Liu ZC, et al., 2025. Single-cell RNA-sequencing-guided reactive oxygen species-scavenging hydrogel design for regeneration of osteoporotic bone. J Zhejiang Univ-Sci B, 26(12):1172-1191.

[22]Infante A, Rodríguez CI, 2018. Osteogenesis and aging: lessons from mesenchymal stem cells. Stem Cell Res Ther, 9:244.

[23]Ishiuchi N, Nakashima A, Doi S, et al., 2020. Hypoxia-preconditioned mesenchymal stem cells prevent renal fibrosis and inflammation in ischemia-reperfusion rats. Stem Cell Res Ther, 11:130.

[24]Kahrizi MS, Mousavi E, Khosravi A, et al., 2023. Recent advances in pre-conditioned mesenchymal stem/stromal cell (MSCs) therapy in organ failure; a comprehensive review of preclinical studies. Stem Cell Res Ther, 14:155.

[25]Kalluri R, Lebleu VS, 2020. The biology, function, and biomedical applications of exosomes. Science, 367(6478):eaau6977.

[26]Kan TY, Li HJ, Hou LL, et al., 2024. Matrix stiffness aggravates osteoarthritis progression through H3K27me3 demethylation induced by mitochondrial damage. iScience, 27(8):110507.

[27]Kfoury Y, Scadden DT, 2015. Mesenchymal cell contributions to the stem cell niche. Cell Stem Cell, 16(3):239-253.

[28]Kushioka J, Chow SKH, Toya M, et al., 2023. Bone regeneration in inflammation with aging and cell-based immunomodulatory therapy. Inflamm Regener, 43:29.

[29]Lee HJ, Lee WJ, Hwang SC, et al., 2021. Chronic inflammation-induced senescence impairs immunomodulatory properties of synovial fluid mesenchymal stem cells in rheumatoid arthritis. Stem Cell Res Ther, 12:502.

[30]Li B, Luan S, Chen J, et al., 2020. The MSC-derived exosomal lncRNA H19 promotes wound healing in diabetic foot ulcers by upregulating PTEN via microRNA-152-3p. Mol Ther Nucleic Acids, 19:814-826.

[31]Li BZ, Xu HX, Han HY, et al., 2018. Exosome-mediated transfer of lncRUNX2-AS1 from multiple myeloma cells to MSCs contributes to osteogenesis. Oncogene, 37(41):5508-5519.

[32]Li BZ, Han HY, Song S, et al., 2019. HOXC10 regulates osteogenesis of mesenchymal stromal cells through interaction with its natural antisense transcript lncHOXC-AS3. Stem Cells, 37(2):247-256.

[33]Li CJ, Xiao Y, Yang M, et al., 2018. Long noncoding RNA Bmncr regulates mesenchymal stem cell fate during skeletal aging. J Clin Invest, 128(12):5251-5266.

[34]Li J, Lu LY, Liu L, et al., 2024. The unique role of bone marrow adipose tissue in ovariectomy-induced bone loss in mice. Endocrine, 83:77-91.

[35]Li QQ, Gao ZW, Chen Y, et al., 2017. The role of mitochondria in osteogenic, adipogenic and chondrogenic differentiation of mesenchymal stem cells. Protein Cell, 8(6):439-445.

[36]Li QH, Lu HY, Zhang MY, et al., 2025. Epigenetic factors associated with peri-implantitis: a review. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 26(7):657-674.

[37]Li T, Jiang HX, Li Y, et al., 2021. Estrogen promotes lncRNA H19 expression to regulate osteogenic differentiation of BMSCs and reduce osteoporosis via miR-532-3p/SIRT1 axis. Mol Cell Endocrinol, 527:111171.

[38]Li XP, Shen HS, Zhang M, et al., 2023. Glycolytic reprogramming in macrophages and MSCs during inflammation. Front Immunol, 14:1199751.

[39]Lin H, Sohn J, Shen H, et al., 2019. Bone marrow mesenchymal stem cells: aging and tissue engineering applications to enhance bone healing. Biomaterials, 203:96-110.

[40]Lin JJ, Xie ZY, Zhang ZQ, et al., 2022. LncRNA MRF drives the regulatory function on monocyte recruitment and polarization through HNRNPD-MCP1 axis in mesenchymal stem cells. J Biomed Sci, 29:73.

[41]Liu Q, Zhang X, Dai LH, et al., 2014. Long noncoding RNA related to cartilage injury promotes chondrocyte extracellular matrix degradation in osteoarthritis. Arthritis Rheumatol, 66(4):969-978.

[42]Liu Q, Zhang X, Hu XQ, et al., 2016a. Circular RNA related to the chondrocyte ECM regulates MMP13 expression by functioning as a miR-136 ‘sponge’ in human cartilage degradation. Sci Rep, 6:22572.

[43]Liu Q, Hu XQ, Zhang X, et al., 2016b. The TMSB4 pseudogene lncRNA functions as a competing endogenous RNA to promote cartilage degradation in human osteoarthritis. Mol Ther, 24(10):1726-1733.

[44]Lotfy A, Aboquella NM, Wang HJ, 2023. Mesenchymal stromal/stem cell (MSC)-derived exosomes in clinical trials. Stem Cell Res Ther, 14:66.

[45]Luo ZH, Ma JX, Zhang W, et al., 2023. Alterations in the microenvironment and the effects produced of TRPV5 in osteoporosis. J Transl Med, 21:327.

[46]Mattick JS, Amaral PP, Carninci P, et al., 2023. Long non-coding RNAs: definitions, functions, challenges and recommendations. Nat Rev Mol Cell Biol, 24(6):430-447.

[47]Moura SR, Freitas J, Ribeiro-Machado C, et al., 2023. Long non-coding RNA H19 regulates matrisome signature and impacts cell behavior on MSC-engineered extracellular matrices. Stem Cell Res Ther, 14:37.

[48]Narasimhan S, al Kawas S, Shetty SR, et al., 2024. Impact of hypoxia on alveolar bone dynamics and remodeling. Heliyon, 10(23):e40868.

[49]Noronha NDC, Mizukami A, Caliári-Oliveira C, et al., 2019. Priming approaches to improve the efficacy of mesenchymal stromal cell-based therapies. Stem Cell Res Ther, 10:131.

[50]Padhi A, Nain AS, 2020. ECM in differentiation: a review of matrix structure, composition and mechanical properties. Ann Biomed Eng, 48(3):1071-1089.

[51]Patil S, Dang K, Zhao X, et al., 2020. Role of lncRNAs and circRNAs in bone metabolism and osteoporosis. Front Genet, 11:584118.

[52]Peppicelli S, Calorini L, Bianchini F, et al., 2025. Acidity and hypoxia of tumor microenvironment, a positive interplay in extracellular vesicle release by tumor cells. Cell Oncol (Dordr), 48:27-41.

[53]Phinney DG, Pittenger MF, 2017. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells, 35(4):851-858.

[54]Redondo J, Bailey S, Kemp KC, et al., 2024. The bone marrow microenvironment in immune-mediated inflammatory diseases: implications for mesenchymal stromal cell-based therapies. Stem Cells Transl Med, 13(3):219-229.

[55]Riegger J, Schoppa A, Ruths L, et al., 2023. Oxidative stress as a key modulator of cell fate decision in osteoarthritis and osteoporosis: a narrative review. Cell Mol Biol Lett, 28:76.

[56]Rolandsson Enes S, Hampton TH, Barua J, et al., 2021. Healthy versus inflamed lung environments differentially affect mesenchymal stromal cells. Eur Respir J, 58(4):2004149.

[57]Sui BD, Hu CH, Liu AQ, et al., 2019. Stem cell-based bone regeneration in diseased microenvironments: challenges and solutions. Biomaterials, 196:18-30.

[58]Sui BD, Zheng CX, Li M, et al., 2020. Epigenetic regulation of mesenchymal stem cell homeostasis. Trends Cell Biol, 30(2):97-116.

[59]Sun MY, Chi GF, Xu JJ, et al., 2018. Extracellular matrix stiffness controls osteogenic differentiation of mesenchymal stem cells mediated by integrin α5. Stem Cell Res Ther, 9:52.

[60]Sun XJ, Fang B, Zhao X, et al., 2014. Preconditioning of mesenchymal stem cells by sevoflurane to improve their therapeutic potential. PLoS One, 9(3):e90667.

[61]Sun Z, Wang SH, Zhao RC, 2014. The roles of mesenchymal stem cells in tumor inflammatory microenvironment. J Hematol Oncol, 7:14.

[62]Tang S, Xie ZY, Wang P, et al., 2019. LncRNA-OG promotes the osteogenic differentiation of bone marrow-derived mesenchymal stem cells under the regulation of hnRNPK. Stem Cells, 37(2):270-283.

[63]Tian YQ, Fang J, Zeng FP, et al., 2022. The role of hypoxic mesenchymal stem cells in tumor immunity. Int Immunopharmacol, 112:109172.

[64]Tong YS, Tu YL, Wang JY, et al., 2025. Mechanisms and therapeutic strategies linking mesenchymal stem cells senescence to osteoporosis. Front Endocrinol (Lausanne), 16:1625806.

[65]Uccelli A, Moretta L, Pistoia V, 2008. Mesenchymal stem cells in health and disease. Nat Rev Immunol, 8(9):726-736.

[66]Wang D, Liu Y, Diao S, et al., 2023. Long non-coding RNAs within macrophage-derived exosomes promote BMSC osteogenesis in a bone fracture rat model. Int J Nanomedicine, 18:1063-1083.

[67]Wang Q, Shen XF, Chen Y, et al., 2021. Osteoblasts-derived exosomes regulate osteoclast differentiation through miR-503-3p/Hpse axis. Acta Histochem, 123(7):151790.

[68]Wang Y, Fang JK, Liu BM, et al., 2022. Reciprocal regulation of mesenchymal stem cells and immune responses. Cell Stem Cell, 29(11):1515-1530.

[69]Wang Y, Hu KL, Liao CD, et al., 2024. Exosomes-shuttled lncRNA SNHG7 by bone marrow mesenchymal stem cells alleviates osteoarthritis through targeting miR-485-5p/FSP1 axis-mediated chondrocytes ferroptosis and inflammation. Tissue Eng Regen Med, 21(8):1203-1216.

[70]Wu ZP, Dai QL, Wang Y, et al., 2025. Emerging roles of the metabolite succinate in bone-related diseases. J Zhejiang Univ-Sci B, 26(12):1137-1155.

[71]Wumiti T, Wang LN, Xu B, et al., 2024. lncTIMP3 promotes osteogenic differentiation of bone marrow mesenchymal stem cells via miR-214/Smad4 axis to relieve postmenopausal osteoporosis. Mol Biol Rep, 51:719.

[72]Xue ZX, Liao YJ, Li Y, 2024. Effects of microenvironment and biological behavior on the paracrine function of stem cells. Genes Dis, 11:135-147.

[73]Yan BH, Li ZC, Su H, et al., 2023. Regulatory mechanisms of autophagy-related ncRNAs in bone metabolic diseases. Front Pharmacol, 14:1178310.

[74]Yang MY, Zheng HS, Xu K, et al., 2022. A novel signature to guide osteosarcoma prognosis and immune microenvironment: cuproptosis-related lncRNA. Front Immunol, 13:919231.

[75]Yang XC, Yang JX, Lei PF, et al., 2019. LncRNA MALAT1 shuttled by bone marrow-derived mesenchymal stem cells-secreted exosomes alleviates osteoporosis through mediating microRNA-34c/SATB2 axis. Aging (Albany NY), 11(20):8777-8791.

[76]Ye Y, Zhao XY, Xu Y, et al., 2021. Hypoxia-inducible non-coding RNAs in mesenchymal stem cell fate and regeneration. Front Dent Med, 2:799716.

[77]You BS, Zhou CL, Yang Y, 2023. MSC-EVs alleviate osteoarthritis by regulating microenvironmental cells in the articular cavity and maintaining cartilage matrix homeostasis. Ageing Res Rev, 85:101864.

[78]Zeng JJ, Deng J, He C, et al., 2024. IGF-1 induces osteogenic differentiation of rat bone marrow mesenchymal stem cells by promoting SOX4 via the MAPK/ERK pathway. Int J Stem Cells, 17(4):418-426.

[79]Zhang CY, Pan L, Zhang HZ, et al., 2023. Osteoblasts-derived exosomal lncRNA-MALAT1 promotes osteoclastogenesis by targeting the miR-124/NFATc1 signaling axis in bone marrow-derived macrophages. Int J Nanomedicine, 18:781-795.

[80]Zhang H, Cai D, Bai X, 2020. Macrophages regulate the progression of osteoarthritis. Osteoarthritis Cartilage, 28(5):555-561.

[81]Zhang SH, Guo JM, He YT, et al., 2025. Roles of lncRNA in the crosstalk between osteogenesis and angiogenesis in the bone microenvironment. J Zhejiang Univ-Sci B (Biomed & Biotechnol), 26(2):107-123.

[82]Zhang WW, Chen L, Wu J, et al., 2019. Long noncoding RNA TUG1 inhibits osteogenesis of bone marrow mesenchymal stem cells via Smad5 after irradiation. Theranostics, 9(8):2198-2208.

[83]Zhang WY, Dong R, Diao S, et al., 2017. Differential long noncoding RNA/mRNA expression profiling and functional network analysis during osteogenic differentiation of human bone marrow mesenchymal stem cells. Stem Cell Res Ther, 8:30.

[84]Zhang YZ, Chen B, Li DZ, et al., 2019. LncRNA NEAT1/miR-29b-3p/BMP1 axis promotes osteogenic differentiation in human bone marrow-derived mesenchymal stem cells. Pathol Res Pract, 215(3):525-531.

[85]Zhivodernikov IV, Kirichenko TV, Markina YV, et al., 2023. Molecular and cellular mechanisms of osteoporosis. Int J Mol Sci, 24(21):15772.

[86]Zhou M, Li SY, Pathak JL, 2019. Pro-inflammatory cytokines and osteocytes. Curr Osteoporos Rep, 17(3):97-104.

[87]Zhu GH, Xia Y, Zhao ZY, et al., 2022. LncRNA XIST from the bone marrow mesenchymal stem cell derived exosome promotes osteosarcoma growth and metastasis through miR-655/ACLY signal. Cancer Cell Int, 22:330.

[88]Zhu XX, Yu JJ, Du J, et al., 2019. LncRNA HOXA‐AS2 positively regulates osteogenesis of mesenchymal stem cells through inactivating NF-κB signalling. J Cell Mol Med, 23(2):1325-1332.

[89]Zhuang WZ, Ge XP, Yang SJ, et al., 2015. Upregulation of lncRNA MEG3 promotes osteogenic differentiation of mesenchymal stem cells from multiple myeloma patients by targeting BMP4 transcription. Stem Cells, 33(6):1985-1997.

Open peer comments: Debate/Discuss/Question/Opinion

<1>

Please provide your name, email address and a comment





Full Text:  <987>

Summary:  <35>

CLC number: 

On-line Access: 2026-10-23

Received: 2025-10-30

Revision Accepted: 2026-04-19

Crosschecked: 0000-00-00

Cited: 0

Clicked: 849

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Ye Chen

https://orcid.org/0000-0003-3671-2504

Jing ZHENG

https://orcid.org/0000-0002-2060-2725

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2026 Journal of Zhejiang University-SCIENCE