粘着斑信号通路调节机体免疫功能的作用和机制研究

  骨髓来源的间充质基质/干细胞（Bone marrow-derived mesenchymal stromal/stem cell, BMSC）是具有多向分化潜能的多能干细胞。BMSC具备调节免疫反应的潜力，通过分泌抗纤维化、抗凋亡和促血管生成的细胞因子和营养因子，在缺血、炎症和免疫失调等疾病的治疗中得到了应用。然而，BMSC具体的免疫调节机制尚未明确，基础研究与临床应用之间仍存在差距，亟需探索新的治疗靶点以提升治疗效果。

  本研究通过脂多糖诱导的急性肺损伤模型和葡聚糖硫酸钠盐诱导的溃疡性结肠炎模型，发现了粘着斑蛋白Pinch在BMSC治疗这两种疾病中发挥关键作用：当BMSC缺失Pinch时，其治疗效果显著降低。在敲除Prx1⁺细胞（主要是BMSC）中的Pinch1和Pinch2两个基因（dKO）后，小鼠在6至8周龄时出现异常死亡现象。对4周龄dKO小鼠尾静脉注射野生型小鼠BMSC后，小鼠体重稳步上升，四肢血肿面积减小，炎症因子水平下降，存活率显著提高。接受BMSC治疗的小鼠骨髓细胞数量增加，肝、肾血流恢复，脾肿大程度减轻，凝血功能和血常规指标恢复正常。BMSC回输治疗还优化了dKO小鼠的造血分化能力，其血液细胞数量恢复到了正常水平。

  单细胞转录组学测序结果显示，Pinch缺失导致骨髓基质系统内多种细胞的比例和功能发生改变；BMSC亚群分布的变化影响了成骨、成脂、补体激活、血管生成、细胞外基质稳态和免疫反应等。此外，Pinch在BMSC调控造血中也发挥重要作用。在dKO小鼠14种骨髓血液细胞亚群中，多个亚群出现显著变化。BMSC中Pinch敲除引起小鼠造血和免疫系统紊乱，激发强烈炎症反应：TNF-a、IL-1b等炎症因子水平升高，免疫相关基因表达异常，特别是Cxcr4基因表达显著降低。通过单细胞转录组学与蛋白质组学测序联合分析，我们发现Pinch参与Cxcl12的合成和分泌，可刺激肝细胞产生Mbl2蛋白。在dKO小鼠的骨髓和血清中，Mbl2蛋白表达量显著降低，抑制凝集素补体途径激活，导致先天免疫功能缺失，对细菌和病毒的易感性升高；这可能是小鼠过早死亡的主要原因。缺失Pinch的小鼠可通过持续补充外源性Mbl2重组蛋白维持其先天免疫功能。

  综上所述，骨髓微环境中粘着斑信号通路对维持机体免疫和造血功能至关重要。本研究证实了BMSC中粘着斑蛋白Pinch通过促进Cxcl12表达，刺激肝细胞生成Mbl2，进而激活凝集素补体通路。本研究首次揭示了Pinch-Cxcl12-Mbl2信号轴在免疫和感染性疾病中的重要作用，该发现可能为相关疾病（包括但不限于脓毒症和炎性肠病）提供全新治疗靶点和治疗策略。

Bone marrow-derived mesenchymal stromal/stem cells (BMSCs) are multipotent stem cells with the potential for multidirectional differentiation. BMSCs have the potential to regulate immune responses by secreting cytokines and growth factors that are anti-fibrotic, anti-apoptotic, and pro-angiogenic, and have been applied in the treatment of ischemia, inflammation, and immune disorder. However, the specific immunomodulatory mechanisms of BMSCs are not yet clear, and there is still a gap between basic research and clinical application, urgently needing exploration of new therapeutic targets to enhance treatment outcomes.

  This study found that the focal adhesion protein Pinch plays a crucial role in the treatment of acute lung injury induced by lipopolysaccharide and ulcerative colitis induced by dextran sulfate sodium in BMSC therapy. The therapeutic effects of BMSCs were significantly reduced when Pinch was absent. After double-knocking out (dKO) the Pinch1 and Pinch2 genes in Prx1⁺ cells (mainly BMSCs) resulted in abnormal deaths in mice at 6 to 8 weeks of age. Injection of wild-type mouse BMSCs into 4-week-old dKO mice resulted in a steady increase in body weight, a reduction in limb hematoma size, a decrease level of inflammatory factors, and a significant improvement of survival rate. Mice treated with BMSCs showed increased bone marrow cell numbers, restored hepatic and renal blood flow, reduced splenomegaly, and normalization of coagulation function and blood routine indicators. BMSC refusion therapy also optimized the hematopoietic differentiation ability of dKO mice, restoring their blood cell count to normal levels.

  Single-cell RNA sequencing results showed that the absence of Pinch led to changes in the proportions and functions of various cells within the bone marrow stromal system. The changes in subpopulations of BMSCs affected osteogenesis, adipogenesis, complement activation, angiogenesis, extracellular matrix homeostasis, and immune response. In addition, Pinch plays an essential role in BMSC regulation of the hematopoiesis. Significant changes were observed in multiple subpopulations among the hematopoietic cell subpopulations. Pinch knockout in BMSCs caused disruption of the mouse hematopoietic and immune systems, triggering a strong inflammatory response, elevation of levels of inflammatory cytokines such as TNF-α, IL-1β, abnormal expression of immune-related genes, especially significant reduction in Cxcr4 gene expression. Through combined single-cell transcriptome sequencing and proteomic analysis, it was found that Pinch is involved in the synthesis and secretion of Cxcl12, stimulating hepatocytes to produce Mbl2 protein. In the bone marrow and serum of dKO mice, the expression level of Mbl2 protein decreased significantly, inhibiting the activation of the lectin complement pathway, leading to innate immune dysfunction and increased susceptibility to bacteria and viruses, which may be the major cause of the premature death. Mice lacking Pinch can maintain their innate immune function by continuously supplementing exogenous Mbl2 recombinant protein.

  In a word, the focal adhesion signaling in the bone marrow niche is vital to maintain immune and hematopoietic functions. The study indicates that the focal adhesion protein Pinch in BMSCs promotes the expression of Cxcl12 and stimulates hepatocytes to produce Mbl2, and thereby activates the lectin complement pathway. This study first demonstrates the important role of the focal adhesion signaling pathway in immune and infectious diseases, and proposes the role of the Pinch-Cxcl12-Mbl2 signaling in immune and infectious diseases, providing new therapeutic targets and strategies for those diseases (such as sepsis and inflammatory bowel disease).

[1] SINGER N G, CAPLAN A I. Mesenchymal stem cells: mechanisms of inflammation[J]. Annu Rev Pathol, 2011, 6: 457-478.
[2] UCCELLI A, MORETTA L, PISTOIA V. Mesenchymal stem cells in health and disease[J]. Nat Rev Immunol, 2008, 8(9): 726-736.
[3] WEISS A R R, DAHLKE M H. Immunomodulation by Mesenchymal Stem Cells (MSCs): Mechanisms of Action of Living, Apoptotic, and Dead MSCs[J]. Front Immunol, 2019, 10: 1191.
[4] WEISSMAN I L. Developmental switches in the immune system[J]. Cell, 1994, 76(2): 207-218.
[5] GOTTS J E, MATTHAY M A. Sepsis: pathophysiology and clinical management[J]. Bmj, 2016, 353: i1585.
[6] GOTTS J E, MATTHAY M A. Cell-based Therapy in Sepsis. A Step Closer[J]. Am J Respir Crit Care Med, 2018, 197(3): 280-281.
[7] BERNARDO M E, FIBBE W E. Mesenchymal stromal cells: sensors and switchers of inflammation[J]. Cell Stem Cell, 2013, 13(4): 392-402.
[8] DI NICOLA M, CARLO-STELLA C, MAGNI M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli[J]. Blood, 2002, 99(10): 3838-3843.
[9] MEZEY É. Human Mesenchymal Stem/Stromal Cells in Immune Regulation and Therapy[J]. Stem Cells Transl Med, 2022, 11(2): 114-134.
[10] BURNHAM A J, DALEY-BAUER L P, HORWITZ E M. Mesenchymal stromal cells in hematopoietic cell transplantation[J]. Blood Adv, 2020, 4(22): 5877-5887.
[11] BOREGOWDA S V, PHINNEY D G. Therapeutic applications of mesenchymal stem cells: current outlook[J]. BioDrugs, 2012, 26(4): 201-208.
[12] NéMETH K, LEELAHAVANICHKUL A, YUEN P S, et al. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production[J]. Nat Med, 2009, 15(1): 42-49.
[13] LIU F, XIE J, ZHANG X, et al. Overexpressing TGF-β1 in mesenchymal stem cells attenuates organ dysfunction during CLP-induced septic mice by reducing macrophage-driven inflammation[J]. Stem Cell Res Ther, 2020, 11(1): 378.
[14] JUAREZ J, BENDALL L, BRADSTOCK K. Chemokines and their receptors as therapeutic targets: the role of the SDF-1/CXCR4 axis[J]. Curr Pharm Des, 2004, 10(11): 1245-1259.
[15] LI M, RANSOHOFF R M. The roles of chemokine CXCL12 in embryonic and brain tumor angiogenesis[J]. Semin Cancer Biol, 2009, 19(2): 111-115.
[16] WüRTH R, BAJETTO A, HARRISON J K, et al. CXCL12 modulation of CXCR4 and CXCR7 activity in human glioblastoma stem-like cells and regulation of the tumor microenvironment[J]. Front Cell Neurosci, 2014, 8: 144.
[17] CHEN S, HE T, ZHONG Y, et al. Roles of focal adhesion proteins in skeleton and diseases[J]. Acta Pharm Sin B, 2023, 13(3): 998-1013.
[18] CHEN S, WU X, LAI Y, et al. Kindlin-2 inhibits Nlrp3 inflammasome activation in nucleus pulposus to maintain homeostasis of the intervertebral disc[J]. Bone Res, 2022, 10(1): 5.
[19] WU X, LAI Y, CHEN S, et al. Kindlin-2 preserves integrity of the articular cartilage to protect against osteoarthritis[J]. Nat Aging, 2022, 2(4): 332-347.
[20] GAO H, ZHONG Y, ZHOU L, et al. Kindlin-2 inhibits TNF/NF-κB-Caspase 8 pathway in hepatocytes to maintain liver development and function[J]. Elife, 2023, 12
[21] XU H, CAO H, XIAO G. Signaling via PINCH: Functions, binding partners and implications in human diseases[J]. Gene, 2016, 594(1): 10-15.
[22] LEI Y, FU X, LI P, et al. LIM domain proteins Pinch1/2 regulate chondrogenesis and bone mass in mice[J]. Bone Res, 2020, 8: 37.
[23] WU X, CHEN M, LIN S, et al. Loss of Pinch Proteins Causes Severe Degenerative Disc Disease-Like Lesions in Mice[J]. Aging Dis, 2023,14(5): 1818-1833.
[24] WANG Y, FANG J, LIU B, et al. Reciprocal regulation of mesenchymal stem cells and immune responses[J]. Cell Stem Cell, 2022, 29(11): 1515-1530.
[25] SHI Y, WANG Y, LI Q, et al. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases[J]. Nat Rev Nephrol, 2018, 14(8): 493-507.
[26] PATEL B K, RAABE M J, LANG E R, et al. Spatial Transcriptomics Reveals Distinct Tissue Niches Linked with Steroid Responsiveness in Acute Gastrointestinal GVHD[J]. Blood, 2023
[27] WU R, LIU C, DENG X, et al. Enhanced alleviation of aGVHD by TGF-β1-modified mesenchymal stem cells in mice through shifting MΦ into M2 phenotype and promoting the differentiation of Treg cells[J]. J Cell Mol Med, 2020, 24(2): 1684-1699.
[28] ROBLES J D, LIU Y P, CAO J, et al. Immunosuppressive mechanisms of human bone marrow derived mesenchymal stromal cells in BALB/c host graft versus host disease murine models[J]. Exp Hematol Oncol, 2015, 4: 13.
[29] VACARU A M, MAZILU A M, DUMITRESCU M, et al. Treatment with Mesenchymal Stromal Cells Overexpressing Fas-Ligand Ameliorates Acute Graft-versus-Host Disease in Mice[J]. Int J Mol Sci, 2022, 23(1): 534.
[30] DE LUCA L, TRINO S, LAURENZANA I, et al. Mesenchymal Stem Cell Derived Extracellular Vesicles: A Role in Hematopoietic Transplantation?[J]. Int J Mol Sci, 2017, 18(5)
[31] GUO L, LAI P, WANG Y, et al. Extracellular vesicles from mesenchymal stem cells prevent contact hypersensitivity through the suppression of Tc1 and Th1 cells and expansion of regulatory T cells[J]. Int Immunopharmacol, 2019, 74: 105663.
[32] GAUTHIER S D, LEBOEUF D, MANUGUERRA-GAGNé R, et al. Stromal-Derived Factor-1α and Interleukin-7 Treatment Improves Homeostatic Proliferation of Naïve CD4(+) T Cells after Allogeneic Stem Cell Transplantation[J]. Biol Blood Marrow Transplant, 2015, 21(10): 1721-1731.
[33] DAL COLLO G, ADAMO A, GATTI A, et al. Functional dosing of mesenchymal stromal cell-derived extracellular vesicles for the prevention of acute graft-versus-host-disease[J]. Stem Cells, 2020, 38(5): 698-711.
[34] LI K L, LI J Y, XIE G L, et al. Exosomes Released From Human Bone Marrow-Derived Mesenchymal Stem Cell Attenuate Acute Graft-Versus-Host Disease After Allogeneic Hematopoietic Stem Cell Transplantation in Mice[J]. Front Cell Dev Biol, 2021, 9: 617589.
[35] ZHU H, LAN L, ZHANG Y, et al. Epidermal growth factor stimulates exosomal microRNA-21 derived from mesenchymal stem cells to ameliorate aGVHD by modulating regulatory T cells[J]. Faseb j, 2020, 34(6): 7372-7386.
[36] TOUIL H, LI R, ZUROFF L, et al. Cross-talk between B cells, microglia and macrophages, and implications to central nervous system compartmentalized inflammation and progressive multiple sclerosis[J]. EBioMedicine, 2023, 96: 104789.
[37] PILIPOVIĆ I, STOJIĆ-VUKANIĆ Z, LEPOSAVIĆ G. Adrenoceptors as potential target for add-on immunomodulatory therapy in multiple sclerosis[J]. Pharmacol Ther, 2023, 243: 108358.
[38] LIU Y, MA Y, DU B, et al. Mesenchymal Stem Cells Attenuated Blood-Brain Barrier Disruption via Downregulation of Aquaporin-4 Expression in EAE Mice[J]. Mol Neurobiol, 2020, 57(9): 3891-3901.
[39] ZHANG J, BULLER B A, ZHANG Z G, et al. Exosomes derived from bone marrow mesenchymal stromal cells promote remyelination and reduce neuroinflammation in the demyelinating central nervous system[J]. Exp Neurol, 2022, 347: 113895.
[40] FAN J, HAN Y, SUN H, et al. Mesenchymal stem cell-derived exosomal microRNA-367-3p alleviates experimental autoimmune encephalomyelitis via inhibition of microglial ferroptosis by targeting EZH2[J]. Biomed Pharmacother, 2023, 162: 114593.
[41] MATHIAN A, ARNAUD L, RUIZ-IRASTORZA G. Is it safe to withdraw low-dose glucocorticoids in SLE patients in remission?[J]. Autoimmun Rev, 2023: 103446.
[42] GAO L, BIRD A K, MEEDNU N, et al. Bone Marrow-Derived Mesenchymal Stem Cells From Patients With Systemic Lupus Erythematosus Have a Senescence-Associated Secretory Phenotype Mediated by a Mitochondrial Antiviral Signaling Protein-Interferon-β Feedback Loop[J]. Arthritis Rheumatol, 2017, 69(8): 1623-1635.
[43] ZHOU K, ZHANG H, JIN O, et al. Transplantation of human bone marrow mesenchymal stem cell ameliorates the autoimmune pathogenesis in MRL/lpr mice[J]. Cell Mol Immunol, 2008, 5(6): 417-424.
[44] LEE H K, KIM H S, KIM J S, et al. CCL2 deficient mesenchymal stem cells fail to establish long-lasting contact with T cells and no longer ameliorate lupus symptoms[J]. Sci Rep, 2017, 7: 41258.
[45] GENG L, TANG X, ZHOU K, et al. MicroRNA-663 induces immune dysregulation by inhibiting TGF-β1 production in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus[J]. Cell Mol Immunol, 2019, 16(3): 260-274.
[46] TAN W, GU Z, LENG J, et al. Let-7f-5p ameliorates inflammation by targeting NLRP3 in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus[J]. Biomed Pharmacother, 2019, 118: 109313.
[47] YANG C, SUN J, TIAN Y, et al. Immunomodulatory Effect of MSCs and MSCs-Derived Extracellular Vesicles in Systemic Lupus Erythematosus[J]. Front Immunol, 2021, 12: 714832.
[48] CHE N, LI X, ZHANG L, et al. Impaired B cell inhibition by lupus bone marrow mesenchymal stem cells is caused by reduced CCL2 expression[J]. J Immunol, 2014, 193(10): 5306-5314.
[49] LEE H K, KIM H S, PYO M, et al. Phorbol ester activates human mesenchymal stem cells to inhibit B cells and ameliorate lupus symptoms in MRL.Fas(lpr) mice[J]. Theranostics, 2020, 10(22): 10186-10199.
[50] LIU H, LI R, LIU T, et al. Immunomodulatory Effects of Mesenchymal Stem Cells and Mesenchymal Stem Cell-Derived Extracellular Vesicles in Rheumatoid Arthritis[J]. Front Immunol, 2020, 11: 1912.
[51] SHAO Y, ZHOU F, HE D, et al. Overexpression of CXCR7 promotes mesenchymal stem cells to repair phosgene-induced acute lung injury in rats[J]. Biomed Pharmacother, 2019, 109: 1233-1239.
[52] WEI S T, HUANG Y C, CHIANG J Y, et al. Gain of CXCR7 function with mesenchymal stem cell therapy ameliorates experimental arthritis via enhancing tissue regeneration and immunomodulation[J]. Stem Cell Res Ther, 2021, 12(1): 314.
[53] ERDMAN R, STAHL R C, ROTHBLUM K, et al. Schwann cell adhesion to a novel heparan sulfate binding site in the N-terminal domain of alpha 4 type V collagen is mediated by syndecan-3[J]. J Biol Chem, 2002, 277(9): 7619-7625.
[54] JONES F K, STEFAN A, KAY A G, et al. Syndecan-3 regulates MSC adhesion, ERK and AKT signalling in vitro and its deletion enhances MSC efficacy in a model of inflammatory arthritis in vivo[J]. Sci Rep, 2020, 10(1): 20487.
[55] TIAN S, YAN Y, QI X, et al. Treatment of Type II Collagen-Induced Rat Rheumatoid Arthritis Model by Interleukin 10 (IL10)-Mesenchymal Stem Cells (BMSCs)[J]. Med Sci Monit, 2019, 25: 2923-2934.
[56] HU Q Y, YUAN Y, LI Y C, et al. Programmed Cell Death Ligand 1-Transfected Mouse Bone Marrow Mesenchymal Stem Cells as Targeted Therapy for Rheumatoid Arthritis[J]. Biomed Res Int, 2021, 2021: 5574282.
[57] CAO Y, BROMBACHER F, TUNYOGI-CSAPO M, et al. Interleukin-4 regulates proteoglycan-induced arthritis by specifically suppressing the innate immune response[J]. Arthritis Rheum, 2007, 56(3): 861-870.
[58] HAIKAL S M, ABDELTAWAB N F, RASHED L A, et al. Combination Therapy of Mesenchymal Stromal Cells and Interleukin-4 Attenuates Rheumatoid Arthritis in a Collagen-Induced Murine Model[J]. Cells, 2019, 8(8)
[59] ALCARAZ M J, GUILLéN M I. Cellular and Molecular Targets of Extracellular Vesicles from Mesenchymal Stem/Stromal Cells in Rheumatoid Arthritis[J]. Stem Cells Transl Med, 2022, 11(12): 1177-1185.
[60] NGUYEN H, NGUYEN H L, LAN P D, et al. Interaction of SARS-CoV-2 with host cells and antibodies: experiment and simulation[J]. Chem Soc Rev, 2023
[61] WANG Y, GAO T, LI W, et al. Engineered clinical-grade mesenchymal stromal cells combating SARS-CoV-2 omicron variants by secreting effective neutralizing antibodies[J]. Cell Biosci, 2023, 13(1): 160.
[62] HAO S, NING K, KUZ C A, et al. SARS-CoV-2 infection of polarized human airway epithelium induces necroptosis that causes airway epithelial barrier dysfunction[J]. J Med Virol, 2023, 95(9): e29076.
[63] ROSSELLO-GELABERT M, GONZALEZ-PUJANA A, IGARTUA M, et al. Clinical progress in MSC-based therapies for the management of severe COVID-19[J]. Cytokine Growth Factor Rev, 2022, 68: 25-36.
[64] XIANG B, CHEN L, WANG X, et al. Transplantation of Menstrual Blood-Derived Mesenchymal Stem Cells Promotes the Repair of LPS-Induced Acute Lung Injury[J]. Int J Mol Sci, 2017, 18(4)
[65] MORRISON T J, JACKSON M V, CUNNINGHAM E K, et al. Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer[J]. Am J Respir Crit Care Med, 2017, 196(10): 1275-1286.
[66] SU Y, SILVA J D, DOHERTY D, et al. Mesenchymal stromal cells-derived extracellular vesicles reprogramme macrophages in ARDS models through the miR-181a-5p-PTEN-pSTAT5-SOCS1 axis[J]. Thorax, 2023, 78(6): 617-630.
[67] MATTOLI S, SCHMIDT M. Investigational Use of Mesenchymal Stem/Stromal Cells and Their Secretome as Add-On Therapy in Severe Respiratory Virus Infections: Challenges and Perspectives[J]. Adv Ther, 2023, 40(6): 2626-2692.
[68] STOKEL-WALKER C. What do we know about the adaptive immune response to covid-19?[J]. Bmj, 2023, 380: 19.
[69] KASPI H, SEMO J, ABRAMOV N, et al. MSC-NTF (NurOwn®) exosomes: a novel therapeutic modality in the mouse LPS-induced ARDS model[J]. Stem Cell Res Ther, 2021, 12(1): 72.
[70] ZHU R, YAN T, FENG Y, et al. Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms[J]. Cell Res, 2021, 31(12): 1244-1262.
[71] SHI L, WANG L, XU R, et al. Mesenchymal stem cell therapy for severe COVID-19[J]. Signal Transduct Target Ther, 2021, 6(1): 339.
[72] BEHESHTI MAAL A, SHAHRBAF M A, SADRI B, et al. Prevalence of hepatobiliary manifestations in inflammatory bowel disease: a GRADE assessed systematic review and meta-analysis on more than 1.7 million patients[J]. J Crohns Colitis, 2023
[73] HULDANI H, MARGIANA R, AHMAD F, et al. Immunotherapy of inflammatory bowel disease (IBD) through mesenchymal stem cells[J]. Int Immunopharmacol, 2022, 107: 108698.
[74] PARK J S, YI T G, PARK J M, et al. Therapeutic effects of mouse bone marrow-derived clonal mesenchymal stem cells in a mouse model of inflammatory bowel disease[J]. J Clin Biochem Nutr, 2015, 57(3): 192-203.
[75] LEE H J, OH S H, JANG H W, et al. Long-Term Effects of Bone Marrow-Derived Mesenchymal Stem Cells in Dextran Sulfate Sodium-Induced Murine Chronic Colitis[J]. Gut Liver, 2016, 10(3): 412-419.
[76] HOFFMAN A M, DOW S W. Concise Review: Stem Cell Trials Using Companion Animal Disease Models[J]. Stem Cells, 2016, 34(7): 1709-1729.
[77] SOONTARARAK S, CHOW L, JOHNSON V, et al. Mesenchymal Stem Cells (MSC) Derived from Induced Pluripotent Stem Cells (iPSC) Equivalent to Adipose-Derived MSC in Promoting Intestinal Healing and Microbiome Normalization in Mouse Inflammatory Bowel Disease Model[J]. Stem Cells Transl Med, 2018, 7(6): 456-467.
[78] XIONG X, CHENG Z, WU F, et al. Berberine in the treatment of ulcerative colitis: A possible pathway through Tuft cells[J]. Biomed Pharmacother, 2021, 134: 111129.
[79] LUZ-CRAWFORD P, KURTE M, BRAVO-ALEGRíA J, et al. Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells[J]. Stem Cell Res Ther, 2013, 4(3): 65.
[80] GONG W, GUO M, HAN Z, et al. Mesenchymal stem cells stimulate intestinal stem cells to repair radiation-induced intestinal injury[J]. Cell Death Dis, 2016, 7(9): e2387.
[81] SCHUMACHER S, VAZQUEZ NUNEZ R, BIERTüMPFEL C, et al. Bottom-up reconstitution of focal adhesion complexes[J]. Febs j, 2022, 289(12): 3360-3373.
[82] REVACH O Y, GROSHEVA I, GEIGER B. Biomechanical regulation of focal adhesion and invadopodia formation[J]. J Cell Sci, 2020, 133(20)
[83] OAKES P W, GARDEL M L. Stressing the limits of focal adhesion mechanosensitivity[J]. Curr Opin Cell Biol, 2014, 30: 68-73.
[84] MISHRA Y G, MANAVATHI B. Focal adhesion dynamics in cellular function and disease[J]. Cell Signal, 2021, 85: 110046.
[85] BOSCH-FORTEA M, MARTíN-BELMONTE F. Mechanosensitive adhesion complexes in epithelial architecture and cancer onset[J]. Curr Opin Cell Biol, 2018, 50: 42-49.
[86] WU S, CHEN M, HUANG J, et al. ORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis through PI3K/Akt Signaling and MAPK-Dependent Focal Adhesion Disassembly[J]. Cancer Res, 2021, 81(4): 986-1000.
[87] ZHAN J, ZHANG H. Kindlins: Roles in development and cancer progression[J]. Int J Biochem Cell Biol, 2018, 98: 93-103.
[88] SCHELL C, ROGG M, SUHM M, et al. The FERM protein EPB41L5 regulates actomyosin contractility and focal adhesion formation to maintain the kidney filtration barrier[J]. Proc Natl Acad Sci U S A, 2017, 114(23): E4621-e4630.
[89] ZENARO E, PIETRONIGRO E, DELLA BIANCA V, et al. Neutrophils promote Alzheimer's disease-like pathology and cognitive decline via LFA-1 integrin[J]. Nat Med, 2015, 21(8): 880-886.
[90] BILDYUG N. Integrins in cardiac hypertrophy: lessons learned from culture systems[J]. ESC Heart Fail, 2021, 8(5): 3634-3642.
[91] HE X, SONG J, CAI Z, et al. Kindlin-2 deficiency induces fatal intestinal obstruction in mice[J]. Theranostics, 2020, 10(14): 6182-6200.
[92] ZHU K, LAI Y, CAO H, et al. Kindlin-2 modulates MafA and β-catenin expression to regulate β-cell function and mass in mice[J]. Nat Commun, 2020, 11(1): 484.
[93] CAO H, YAN Q, WANG D, et al. Focal adhesion protein Kindlin-2 regulates bone homeostasis in mice[J]. Bone Res, 2020, 8: 2.
[94] LEGERSTEE K, HOUTSMULLER A B. A Layered View on Focal Adhesions[J]. Biology (Basel), 2021, 10(11)
[95] HORTON E R, BYRON A, ASKARI J A, et al. Definition of a consensus integrin adhesome and its dynamics during adhesion complex assembly and disassembly[J]. Nat Cell Biol, 2015, 17(12): 1577-1587.
[96] LUO B H, CARMAN C V, SPRINGER T A. Structural basis of integrin regulation and signaling[J]. Annu Rev Immunol, 2007, 25: 619-647.
[97] SUN Z, COSTELL M, FäSSLER R. Integrin activation by talin, kindlin and mechanical forces[J]. Nat Cell Biol, 2019, 21(1): 25-31.
[98] MURPHY K N, BRINKWORTH A J. Manipulation of Focal Adhesion Signaling by Pathogenic Microbes[J]. Int J Mol Sci, 2021, 22(3)
[99] MAKRIS E A, GOMOLL A H, MALIZOS K N, et al. Repair and tissue engineering techniques for articular cartilage[J]. Nat Rev Rheumatol, 2015, 11(1): 21-34.
[100] KATZ J N, ARANT K R, LOESER R F. Diagnosis and Treatment of Hip and Knee Osteoarthritis: A Review[J]. Jama, 2021, 325(6): 568-578.
[101] ZHENG L, ZHANG Z, SHENG P, et al. The role of metabolism in chondrocyte dysfunction and the progression of osteoarthritis[J]. Ageing Res Rev, 2021, 66: 101249.
[102] WOLFENSON H, LAVELIN I, GEIGER B. Dynamic regulation of the structure and functions of integrin adhesions[J]. Dev Cell, 2013, 24(5): 447-458.
[103] TIAN J, ZHANG F J, LEI G H. Role of integrins and their ligands in osteoarthritic cartilage[J]. Rheumatol Int, 2015, 35(5): 787-798.
[104] LOESER R F. Integrins and chondrocyte-matrix interactions in articular cartilage[J]. Matrix Biol, 2014, 39: 11-16.
[105] LOESER R F, CARLSON C S, MCGEE M P. Expression of beta 1 integrins by cultured articular chondrocytes and in osteoarthritic cartilage[J]. Exp Cell Res, 1995, 217(2): 248-257.
[106] WANG Q, ONUMA K, LIU C, et al. Dysregulated integrin αVβ3 and CD47 signaling promotes joint inflammation, cartilage breakdown, and progression of osteoarthritis[J]. JCI Insight, 2019, 4(18): e128616.
[107] ANDERSEN C, UVEBRANT K, MORI Y, et al. Human integrin α10β1-selected mesenchymal stem cells home to cartilage defects in the rabbit knee and assume a chondrocyte-like phenotype[J]. Stem Cell Res Ther, 2022, 13(1): 206.
[108] ALMONTE-BECERRIL M, GIMENO L I, VILLARROYA O, et al. Genetic abrogation of the fibronectin-α5β1 integrin interaction in articular cartilage aggravates osteoarthritis in mice[J]. PLoS One, 2018, 13(6): e0198559.
[109] RADUCANU A, HUNZIKER E B, DROSSE I, et al. Beta1 integrin deficiency results in multiple abnormalities of the knee joint[J]. J Biol Chem, 2009, 284(35): 23780-23792.
[110] TAPIAL MARTíNEZ P, LóPEZ NAVAJAS P, LIETHA D. FAK Structure and Regulation by Membrane Interactions and Force in Focal Adhesions[J]. Biomolecules, 2020, 10(2)
[111] WU T J, LIN C Y, TSAI C H, et al. Glucose suppresses IL-1β-induced MMP-1 expression through the FAK, MEK, ERK, and AP-1 signaling pathways[J]. Environ Toxicol, 2018, 33(10): 1061-1068.
[112] SHAHRARA S, CASTRO-RUEDA H P, HAINES G K, et al. Differential expression of the FAK family kinases in rheumatoid arthritis and osteoarthritis synovial tissues[J]. Arthritis Res Ther, 2007, 9(5): R112.
[113] MA S N, XIE Z G, GUO Y, et al. Effect of Acupotomy on FAK-PI3K Signaling Pathways in KOA Rabbit Articular Cartilages[J]. Evid Based Complement Alternat Med, 2017, 2017: 4535326.
[114] ZHANG C, ZHU M, WANG H, et al. LOXL2 attenuates osteoarthritis through inactivating Integrin/FAK signaling[J]. Sci Rep, 2021, 11(1): 17020.
[115] WU C, JIAO H, LAI Y, et al. Kindlin-2 controls TGF-β signalling and Sox9 expression to regulate chondrogenesis[J]. Nat Commun, 2015, 6: 7531.
[116] WU X, QU M, GONG W, et al. Kindlin-2 deletion in osteoprogenitors causes severe chondrodysplasia and low-turnover osteopenia in mice[J]. J Orthop Translat, 2022, 32: 41-48.
[117] KERR B A, SHI L, JINNAH A H, et al. Kindlin-3 mutation in mesenchymal stem cells results in enhanced chondrogenesis[J]. Exp Cell Res, 2021, 399(2): 112456.
[118] KOSHIMIZU T, KAWAI M, KONDOU H, et al. Vinculin functions as regulator of chondrogenesis[J]. J Biol Chem, 2012, 287(19): 15760-15775.
[119] GUO S S, AU T Y K, WYNN S, et al. β1 Integrin regulates convergent extension in mouse notogenesis, ensures notochord integrity and the morphogenesis of vertebrae and intervertebral discs[J]. Development, 2020, 147(22)
[120] KANDA Y, YURUBE T, MORITA Y, et al. Delayed notochordal cell disappearance through integrin α5β1 mechanotransduction during ex-vivo dynamic loading-induced intervertebral disc degeneration[J]. J Orthop Res, 2021, 39(9): 1933-1944.
[121] KURAKAWA T, KAKUTANI K, MORITA Y, et al. Functional impact of integrin α5β1 on the homeostasis of intervertebral discs: a study of mechanotransduction pathways using a novel dynamic loading organ culture system[J]. Spine J, 2015, 15(3): 417-426.
[122] TRAN C M, SCHOEPFLIN Z R, MARKOVA D Z, et al. CCN2 suppresses catabolic effects of interleukin-1β through α5β1 and αVβ3 integrins in nucleus pulposus cells: implications in intervertebral disc degeneration[J]. J Biol Chem, 2014, 289(11): 7374-7387.
[123] ZHAO C M, CHEN Q, ZHANG W J, et al. 17β-Estradiol Protects Rat Annulus Fibrosus Cells Against Apoptosis via α1 Integrin-Mediated Adhesion to Type I Collagen: An In-vitro Study[J]. Med Sci Monit, 2016, 22: 1375-1383.
[124] WU X, CHEN M, LIN S, et al. Loss of Pinch Proteins Causes Severe Degenerative Disc Disease-Like Lesions in Mice[J]. Aging Dis, 2023, 14(5): 1818-1833.
[125] GAO G, LI H, HUANG Y, et al. Periodic Mechanical Stress Induces Extracellular Matrix Expression and Migration of Rat Nucleus Pulposus Cells Through Src-GIT1-ERK1/2 Signaling Pathway[J]. Cell Physiol Biochem, 2018, 50(4): 1510-1521.
[126] HUANG B R, CHEN T S, BAU D T, et al. EGFR is a pivotal regulator of thrombin-mediated inflammation in primary human nucleus pulposus culture[J]. Sci Rep, 2017, 7(1): 8578.
[127] YE D, LIANG W, DAI L, et al. Moderate Fluid Shear Stress Could Regulate the Cytoskeleton of Nucleus Pulposus and Surrounding Inflammatory Mediators by Activating the FAK-MEK5-ERK5-cFos-AP1 Signaling Pathway[J]. Dis Markers, 2018, 2018: 9405738.
[128] HUANG B R, BAU D T, CHEN T S, et al. Pro-Inflammatory Stimuli Influence Expression of Intercellular Adhesion Molecule 1 in Human Anulus Fibrosus Cells through FAK/ERK/GSK3 and PKCδ Signaling Pathways[J]. Int J Mol Sci, 2018, 20(1)
[129] ZHANG Z, MU Y, ZHANG J, et al. Kindlin-2 Is Essential for Preserving Integrity of the Developing Heart and Preventing Ventricular Rupture[J]. Circulation, 2019, 139(12): 1554-1556.
[130] BOCK-MARQUETTE I, SAXENA A, WHITE M D, et al. Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair[J]. Nature, 2004, 432(7016): 466-472.
[131] LIANG X, SUN Y, YE M, et al. Targeted ablation of PINCH1 and PINCH2 from murine myocardium results in dilated cardiomyopathy and early postnatal lethality[J]. Circulation, 2009, 120(7): 568-576.
[132] GAO H, ZHOU L, ZHONG Y, et al. Kindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice[J]. Nat Commun, 2022, 13(1): 1025.
[133] GAO H, ZHONG Y, DING Z, et al. Pinch Loss Ameliorates Obesity, Glucose Intolerance, and Fatty Liver by Modulating Adipocyte Apoptosis in Mice[J]. Diabetes, 2021, 70(11): 2492-2505.
[134] FRIDENSHTEĬN A, PIATETSKIĬ S, II, PETRAKOVA K V. [Osteogenesis in transplants of bone marrow cells][J]. Arkh Anat Gistol Embriol, 1969, 56(3): 3-11.
[135] DOMINICI M, LE BLANC K, MUELLER I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement[J]. Cytotherapy, 2006, 8(4): 315-317.
[136] CHISWELL B P, ZHANG R, MURPHY J W, et al. The structural basis of integrin-linked kinase-PINCH interactions[J]. Proc Natl Acad Sci U S A, 2008, 105(52): 20677-20682.
[137] STANCHI F, BORDOY R, KUDLACEK O, et al. Consequences of loss of PINCH2 expression in mice[J]. J Cell Sci, 2005, 118(Pt 24): 5899-5910.
[138] SANCHEZ-GURMACHES J, HSIAO W Y, GUERTIN D A. Highly selective in vivo labeling of subcutaneous white adipocyte precursors with Prx1-Cre[J]. Stem Cell Reports, 2015, 4(4): 541-550.
[139] WILK K, YEH S A, MORTENSEN L J, et al. Postnatal Calvarial Skeletal Stem Cells Expressing PRX1 Reside Exclusively in the Calvarial Sutures and Are Required for Bone Regeneration[J]. Stem Cell Reports, 2017, 8(4): 933-946.
[140] BUDGUDE P, KALE V, VAIDYA A. Pharmacological Inhibition of p38 MAPK Rejuvenates Bone Marrow Derived-Mesenchymal Stromal Cells and Boosts their Hematopoietic Stem Cell-Supportive Ability[J]. Stem Cell Rev Rep, 2021, 17(6): 2210-2222.
[141] HAJISHENGALLIS G, LI X, CHAVAKIS T. Immunometabolic control of hematopoiesis[J]. Mol Aspects Med, 2021, 77: 100923.
[142] ZHOU B O, YUE R, MURPHY M M, et al. Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow[J]. Cell Stem Cell, 2014, 15(2): 154-168.
[143] OMATSU Y. Cellular niches for hematopoietic stem cells in bone marrow under normal and malignant conditions[J]. Inflamm Regen, 2023, 43(1): 15.
[144] COMAZZETTO S, MURPHY M M, BERTO S, et al. Restricted Hematopoietic Progenitors and Erythropoiesis Require SCF from Leptin Receptor+ Niche Cells in the Bone Marrow[J]. Cell Stem Cell, 2019, 24(3): 477-486.e476.
[145] GIRI J, DAS R, NYLEN E, et al. CCL2 and CXCL12 Derived from Mesenchymal Stromal Cells Cooperatively Polarize IL-10+ Tissue Macrophages to Mitigate Gut Injury[J]. Cell Rep, 2020, 30(6): 1923-1934.e1924.
[146] SCHOFIELD R. The relationship between the spleen colony-forming cell and the haemopoietic stem cell[J]. Blood Cells, 1978, 4(1-2): 7-25.
[147] WANG Y, LAN W, XU M, et al. Cancer-associated fibroblast-derived SDF-1 induces epithelial-mesenchymal transition of lung adenocarcinoma via CXCR4/β-catenin/PPARδ signalling[J]. Cell Death Dis, 2021, 12(2): 214.
[148] REITER J, DRUMMOND S, SAMMOUR I, et al. Stromal derived factor-1 mediates the lung regenerative effects of mesenchymal stem cells in a rodent model of bronchopulmonary dysplasia[J]. Respir Res, 2017, 18(1): 137.
[149] BAČENKOVá D, TREBUŇOVá M, MOROCHOVIČ R, et al. Interaction between Mesenchymal Stem Cells and the Immune System in Rheumatoid Arthritis[J]. Pharmaceuticals (Basel), 2022, 15(8)
[150] KALKAL M, TIWARI M, THAKUR R S, et al. Mesenchymal Stem Cells: A Novel Therapeutic Approach to Enhance Protective Immunomodulation and Erythropoietic Recovery in Malaria[J]. Stem Cell Rev Rep, 2021, 17(6): 1993-2002.
[151] ZANGI L, MARGALIT R, REICH-ZELIGER S, et al. Direct imaging of immune rejection and memory induction by allogeneic mesenchymal stromal cells[J]. Stem Cells, 2009, 27(11): 2865-2874.
[152] SKRAHIN A, JENKINS H E, HUREVICH H, et al. Effectiveness of a novel cellular therapy to treat multidrug-resistant tuberculosis[J]. Int J Mycobacteriol, 2016, 5 Suppl 1: S23.
[153] ZHANG Z, FU J, XU X, et al. Safety and immunological responses to human mesenchymal stem cell therapy in difficult-to-treat HIV-1-infected patients[J]. Aids, 2013, 27(8): 1283-1293.
[154] TRAGGIAI E, VOLPI S, SCHENA F, et al. Bone marrow-derived mesenchymal stem cells induce both polyclonal expansion and differentiation of B cells isolated from healthy donors and systemic lupus erythematosus patients[J]. Stem Cells, 2008, 26(2): 562-569.
[155] JI Y R, YANG Z X, HAN Z B, et al. Mesenchymal stem cells support proliferation and terminal differentiation of B cells[J]. Cell Physiol Biochem, 2012, 30(6): 1526-1537.
[156] RABANI R, VOLCHUK A, JERKIC M, et al. Mesenchymal stem cells enhance NOX2-dependent reactive oxygen species production and bacterial killing in macrophages during sepsis[J]. Eur Respir J, 2018, 51(4)
[157] MITEVA K, PAPPRITZ K, EL-SHAFEEY M, et al. Mesenchymal Stromal Cells Modulate Monocytes Trafficking in Coxsackievirus B3-Induced Myocarditis[J]. Stem Cells Transl Med, 2017, 6(4): 1249-1261.
[158] HOLERS V M. Complement therapeutics are coming of age in rheumatology[J]. Nat Rev Rheumatol, 2023(8): 470-485.
[159] ZHENG D, OH S H, JUNG Y, et al. Oval cell response in 2-acetylaminofluorene/partial hepatectomy rat is attenuated by short interfering RNA targeted to stromal cell-derived factor-1[J]. Am J Pathol, 2006, 169(6): 2066-2074.
[160] BARRATT J, LAFAYETTE R A, ZHANG H, et al. IgA nephropathy: the lectin pathway and implications for targeted therapy[J]. Kidney Int, 2023(2): 254-264.
[161] EISEN D P, MINCHINTON R M. Impact of mannose-binding lectin on susceptibility to infectious diseases[J]. Clin Infect Dis, 2003, 37(11): 1496-1505.
[162] KALIA N, SINGH J, KAUR M. The ambiguous role of mannose-binding lectin (MBL) in human immunity[J]. Open Med (Wars), 2021, 16(1): 299-310.
[163] SINGH H, JADHAV S, CHAUWARE V. Impact of MBL-2 coding region polymorphism on modulation of HAND and HIV-1 acquisition[J]. Microb Pathog, 2021, 160: 105163.
[164] GUPTA A, GUPTA G S. Status of mannose-binding lectin (MBL) and complement system in COVID-19 patients and therapeutic applications of antiviral plant MBLs[J]. Mol Cell Biochem, 2021, 476(8): 2917-2942.
[165] VALDIMARSSON H, STEFANSSON M, VIKINGSDOTTIR T, et al. Reconstitution of opsonizing activity by infusion of mannan-binding lectin (MBL) to MBL-deficient humans[J]. Scand J Immunol, 1998, 48(2): 116-123.
[166] GARRED P, PRESSLER T, LANNG S, et al. Mannose-binding lectin (MBL) therapy in an MBL-deficient patient with severe cystic fibrosis lung disease[J]. Pediatr Pulmonol, 2002, 33(3): 201-207.
[167] ZENG Q, KO C H, SIU W S, et al. Inhibitory effect of different Dendrobium species on LPS-induced inflammation in macrophages via suppression of MAPK pathways[J]. Chin J Nat Med, 2018, 16(7): 481-489.
[168] LIU T C, STAPPENBECK T S. Genetics and Pathogenesis of Inflammatory Bowel Disease[J]. Annu Rev Pathol, 2016, 11: 127-148.
[169] CAO L, XU H, WANG G, et al. Extracellular vesicles derived from bone marrow mesenchymal stem cells attenuate dextran sodium sulfate-induced ulcerative colitis by promoting M2 macrophage polarization[J]. Int Immunopharmacol, 2019, 72: 264-274.
[170] LI Y L, QIN S Y, LI Q, et al. Jinzhen Oral Liquid alleviates lipopolysaccharide-induced acute lung injury through modulating TLR4/MyD88/NF-κB pathway[J]. Phytomedicine, 2023, 114: 154744.
[171] PERLEE D, VAN VUGHT L A, SCICLUNA B P, et al. Intravenous Infusion of Human Adipose Mesenchymal Stem Cells Modifies the Host Response to Lipopolysaccharide in Humans: A Randomized, Single-Blind, Parallel Group, Placebo Controlled Trial[J]. Stem Cells, 2018, 36(11): 1778-1788.
[172] MATTHAY M A, CALFEE C S, ZHUO H, et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial[J]. Lancet Respir Med, 2019, 7(2): 154-162.
[173] YANG X, YU Y, XU J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study[J]. Lancet Respir Med, 2020, 8(5): 475-481.
[174] YOUSEFI DEHBIDI M, GOODARZI N, AZHDARI M H, et al. Mesenchymal stem cells and their derived exosomes to combat Covid-19[J]. Rev Med Virol, 2022, 32(2): e2281.