Exploring the kidney-tonifying effect of Qi-Xian Decoction for asthma treatment by modulating the proliferation and migration of endogenous BMSCs

Abstract

Traditional Chinese medicine (TCM) establishes that the kidney serves vital systemic functions and its deficiency represents a fundamental factor influencing various diseases, including asthma. The kidney-tonifying method represents a widely implemented clinical approach in TCM to address kidney deficiency. This study hypothesized that bone marrow mesenchymal stem cells (BMSCs) function as key contributors to the kidney-tonifying method. An ovalbumin (OVA)-induced asthma mouse model received treatment with the traditional kidney-tonifying formula, Qi-Xian decoction (QXD). QXD demonstrated significant therapeutic efficacy, enhanced BMSC proliferation in mouse bone marrow, and facilitated their migration to lung tissues. Inhibition of the CXCL12/CXCR4 axis diminished the QXD-induced migration of endogenous BMSCs and reduced QXD’s efficacy in asthma treatment. QXD-containing serum enhanced BMSC proliferation and promoted CXCL12-induced BMSC migration in vitro. These findings indicate that endogenous BMSCs may serve as a crucial mediator in the therapeutic effects of the kidney-tonifying method. Furthermore, the mild and sustained stimulation of production and enhanced homing of endogenous BMSCs presents a potential novel approach for effective asthma treatment.

Keywords

Kidney in traditional Chinese medicine / Bone marrow mesenchymal stem cell / Asthma, Endogenous / Kidney-tonifying method

References

[1] Geng Y, Wang W, Zhang J, et al. Effects of Traditional Chinese Medicine herbs for tonifying Qi and kidney, and replenishing spleen on intermittent asthma in children aged 2 to 5 years old. J Tradit Chin Med. 2016; 36(1):32-38. https://doi.org/10.1016/s0254-6272(16)30005-x.

[2] Li W, Ye B, Huang Z, et al. Effects of kidney tonic herbs for primary osteoporosis: a systematic review and meta-analysis. Medicine. 2023; 102(43):e35061. https://doi.org/10.1097/md.0000000000035061.

[3] Chen SY, Xiao SJ, Lin YN, et al. Clinical efficacy and transcriptomic analysis of Congrong Shujing Granules (苁蓉舒痉颗粒) in patients with Parkinson’s disease and syndrome of Shen (kidney) essence deficiency. Chin J Integr Med. 2020; 26(6):412-419. https://doi.org/10.1007/s11655-020-3080-0.

[4] Shu B, Shi Q, Wang YJ. Shen (Kidney)-tonifying principle for primary osteoporosis: to treat both the disease and the Chinese medicine syndrome. Chin J Integr Med. 2015; 21(9):656-661. https://doi.org/10.1007/s11655-015-2306-z.

[5] Sun H, Xiao D, Liu W, et al. Well-known polypeptides of deer antler velvet with key actives: modern pharmacological advances. Naunyn Schmiedeberg's Arch Pharmacol. 2024; 397(1):15-31. https://doi.org/10.1007/s00210-023-02642-y.

[6] Wang K, Li J, Zheng X, et al. The pharmacological effects and safety of the raw and prepared folium of Epimedium brevicornu Maxim on improving kidney-Yang deficiency syndrome and sexual dysfunction. Front Pharmacol. 2023;14:1233468. https://doi.org/10.3389/fphar.2023.1233468.

[7] Fan L, Peng Y, Wang J, et al. Total glycosides from stems of Cistanche tubulosa alleviate depression-like behaviors: bidirectional interaction of the phytochemicals and gut microbiota. Phytomedicine. 2021;83:153471. https://doi.org/10.1016/j.phymed.2021.153471.

[8] Xu TT, Jin HT, Tong PJ. Essence of “Shen (kidney) controlling bones”: conceptual analysis based on hypothalamic-pituitary-adrenal-osteo-related cells axis. Chin J Integr Med. 2018; 24(11):806-808. https://doi.org/10.1007/s11655-018-2930-x.

[9] Wang K, Zhu H, Yang L, et al.miR-139 promotes homing of bone marrow mesenchymal stem cells (BMSCs) to lung tissues of asthmatic rats to inhibit inflammatory response of Th2 cells by down-regulating Notch1/Hes1 pathway. Chin J Cell Mol Immunol. 2021; 37(2):97-104.

[10] Brown JM, Nemeth K, Kushnir-Sukhov NM, et al. Bone marrow stromal cells inhibit mast cell function via a COX2-dependent mechanism. Clin Exp Allergy. 2011; 41(4):526-534. https://doi.org/10.1111/j.1365-2222.2010.03685.x.

[11] Wang Z, Wu Y, Zhao Z, et al. Study on transorgan regulation of intervertebral disc and extra-skeletal organs through exosomes derived from bone marrow mesenchymal stem cells. Front Cell Dev Biol. 2021;9:741183. https://doi.org/10.3389/fcell.2021.741183.

[12] Stroncek DF, Sabatino M, Ren J, et al. Establishing a bone marrow stromal cell transplant program at the national institutes of health clinical center. Tissue Eng Part B Rev. 2014; 20(3):200-205. https://doi.org/10.1089/ten.teb.2013.0529.

[13] Boldrini-Leite LM, Michelotto PV Jr, de Moura SAB, et al. Lung tissue damage associated with allergic asthma in BALB/c mice could be controlled with a single injection of mesenchymal stem cells from human bone marrow up to 14 d after transplantation. Cell Transplant. 2020;29:096368972091325. https://doi.org/10.1177/0963689720913254.

[14] Ren YB, Huang JH, Cai WJ, et al. Shen-Jing as a Chinese medicine concept might be a counterpart of stem cells in regenerative medicine. Chin J Integr Med. 2019; 25(1):64-70. https://doi.org/10.1007/s11655-015-2136-z.

[15] Bi J, Chen Q, Hang J, et al. Randomized controlled double blind multicenter clinical study on treatment of bronchial asthma in remission stage with Qixian Qingming Granules. Chin Archives Tradit Chin Med. 2020; 35(12):6416-6420.

[16] Tang L, Zhu L, Zhang W, et al. Qi-Xian decoction upregulated E-cadherin expression in human lung epithelial cells and ovalbumin-challenged mice by inhibiting reactive oxygen species-mediated extracellular-signal-regulated kinase (ERK) activation. Med Sci Monit. 2020;26:e922003. https://doi.org/10.12659/msm.922003.

[17] Soleimani M, Nadri S. A protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow. Nat Protoc. 2009; 4(1):102-106. https://doi.org/10.1038/nprot.2008.221.

[18] Zhang B, Li MY, Luo XM, et al. Analysis of the chemical components of Qixianqingming granules and their metabolites in rats by UPLC-ESI-Q-TOF-MS. J Mass Spectrom. 2020;55:e4484. https://doi.org/10.1002/jms.4484.

[19] Zhao FY, Cheng TY, Yang L, et al. G-CSF inhibits pulmonary fibrosis by promoting BMSC homing to the lungs via SDF-1/CXCR4 chemotaxis. Sci Rep. 2020;10:10515. https://doi.org/10.1038/s41598-020-65580-2.

[20] Ni ZH, Tang JH, Chen G, et al. Resveratrol inhibits mucus overproduction and MUC5AC expression in a murine model of asthma. Mol Med Rep. 2016; 13(1):287-294. https://doi.org/10.3892/mmr.2015.4520.

[21] Moriuchi M, Moriuchi H, Margolis DM, et al. USF/c-myc enhances while Yin-Yang 1 suppresses, the promoter activity of CXCR4, a coreceptor for HIV-1 entry. J Immunol. 1999; 162(10):5986-5992. https://doi.org/10.4049/jimmunol.162.10.5986.

[22] Lee BC, Lee TH, Zagozdzon R, et al. Carboxyl-terminal src kinase homologous kinase negatively regulates the chemokine receptor CXCR4 through YY1 and impairs CXCR4/CXCL12 (SDF-1α)-mediated breast cancer cell migration. Cancer Res. 2005; 65(7):2840-2845. https://doi.org/10.1158/0008-5472.can-04-3309.

[23] Xu J, Fu L, Deng J, et al. miR-301a deficiency attenuates the macrophage migration and phagocytosis through YY1/CXCR4 pathway. Cells. 2022; 11(24):3952. https://doi.org/10.3390/cells11243952.

[24] Zhu Z, Zhang G, Li D, et al. Silencing of specificity protein 1 protects H9c2 cells against lipopolysaccharide-induced injury via binding to the promoter of chemokine CXC receptor 4 and suppressing NF-κB signaling. Bioengineered. 2022; 13(2):3395-3409. https://doi.org/10.1080/21655979.2022.2026548.

[25] Sheng XF, Hong LL, Fan L, et al. Circular RNA PVT 1 regulates cell proliferation, migration, and apoptosis by stabilizing c-myc and downstream target CXCR4 expression in acute myeloid leukemia. Tjh. 2023; 40(2):82-91. https://doi.org/10.4274/tjh.galenos.2023.2022.0435.

[26] Kragesteen BK, Giladi A, David E, et al. The transcriptional and regulatory identity of erythropoietin producing cells. Nat Med. 2023; 29(5):1191-1200. https://doi.org/10.1038/s41591-023-02314-7.

[27] Balzer MS, Rohacs T, Susztak K. How many cell types are in the kidney and what do they do? Annu Rev Physiol. 2022; 84:507-531. https://doi.org/10.1146/annurev-physiol-052521-121841.

[28] Zhu H, Wang K, Zhu S, et al. [ The increased expression of stromal cell-derived factor-1 (SDF-1) alleviates airway inflammation in asthmatic rats by promoting the migration of bone marrow mesenchymal stem cells (BMSCs)]. Chin J Cell Mol Immunol. 2023; 39(3):213-219.

[29] Cui J, Ning LJ, Wu FP, et al. Biomechanically and biochemically functional scaffold for recruitment of endogenous stem cells to promote tendon regeneration. NPJ Regen Med. 2022;7:26. https://doi.org/10.1038/s41536-022-00220-z.

[30] Li G, Wang Q, Liu H, et al. Fabricating composite cell sheets for wound healing: cell sheets based on the communication between BMSCs and HFSCs facilitate full-thickness cutaneous wound healing. Tissue Eng Regen Med. 2024; 21(3):421-435. https://doi.org/10.1007/s13770-023-00614-0.

[31] Zhong Z, Li K, Shen C, et al. Erythropoietin improves pulmonary hypertension by promoting the homing and differentiation of bone marrow mesenchymal stem cells in lung tissue. Hum Cell. 2024; 37(1):214-228. https://doi.org/10.1007/s13577-023-01009-y.

[32] Wang Y, Wang J, Gao R, et al. Biomimetic glycopeptide hydrogel coated PCL/nHA scaffold for enhanced cranial bone regeneration via macrophage M2 polarization-induced osteo-immunomodulation. Biomaterials. 2022;285:121538. https://doi.org/10.1016/j.biomaterials.2022.121538.

[33] Guo K, Yao X, Wu W, et al. HIF-1α/SDF-1/CXCR4 axis reduces neuronal apoptosis via enhancing the bone marrow-derived mesenchymal stromal cell migration in rats with traumatic brain injury. Exp Mol Pathol. 2020;114:104416. https://doi.org/10.1016/j.yexmp.2020.104416.

[34] He H, Yuan Y, Wu Y, et al. Exoskeleton partial-coated stem cells for infarcted myocardium restoring. Adv Mater. 2023; 35(52):2307169. https://doi.org/10.1002/adma.202307169.

[35] Matricali GA, Dereymaeker GP and Luyten FP. Donor site morbidity after articular cartilage repair procedures: a review. Acta Orthop Belg. 2010; 76(5):669-674.

[36] Desai S, Jayasuriya CT. Implementation of endogenous and exogenous mesenchymal progenitor cells for skeletal tissue regeneration and repair. Bioengineering. 2020; 7(3):86. https://doi.org/10.3390/bioengineering7030086.

[37] Chu DT, Phuong TNT, Le Bao Tien N, et al. An update on the progress of isolation, culture, storage, and clinical application of human bone marrow mesenchymal stem/stromal cells. Int J Mol Sci. 2020; 21(3):708. https://doi.org/10.3390/ijms21030708.

[38] Su G, Liu L, Yang L, et al. Homing of endogenous bone marrow mesenchymal stem cells to rat infarcted myocardium via ultrasound-mediated recombinant SDF-1α adenovirus in microbubbles. Oncotarget. 2018; 9(1):477-487. https://doi.org/10.18632/oncotarget.23068.

[39] Wei S, Wang Y, Sun Y, et al. Biodegradable silk fibroin scaffold doped with mineralized collagen induces bone regeneration in rat cranial defects. Int J Biol Macromol. 2023;235:123861. https://doi.org/10.1016/j.ijbiomac.2023.123861.

[40] Arthur A, Gronthos S. Clinical application of bone marrow mesenchymal stem/stromal cells to repair skeletal tissue. Int J Mol Sci. 2020; 21(24):9759. https://doi.org/10.3390/ijms21249759.

[41] Yuan JY, Wang XY, Tong ZY, et al. Promising therapeutic functions of bone marrow mesenchymal stem cells derived-exosome in asthma. Can Respir J. 2022;2022:1485719. https://doi.org/10.1155/2022/1485719.

[42] Cruz FF, Borg ZD, Goodwin M, et al. Systemic administration of human bone marrow-derived mesenchymal stromal cell extracellular vesicles ameliorates Aspergillus hyphal extract-induced allergic airway inflammation in immunocompetent mice. Stem Cells Transl Med. 2015; 4(11):1302-1316. https://doi.org/10.5966/sctm.2014-0280.

[43] Song J, Zhu XM, Wei QY. MSCs reduce airway remodeling in the lungs of asthmatic rats through the Wnt/beta-catenin signaling pathway. Eur Rev Med Pharmacol Sci. 2020; 24(21):11199-11211.

[44] Hu Y, Wang MQ, Xie J, et al et al., Exposure to ephedrine attenuates Th1/Th2 imbalance underlying OVA-induced asthma through airway epithelial cell-derived exosomal lnc-TRPM2-AS. Chin J Nat Med. 2024; 22(6):530-540. https://doi.org/10.1016/S1875-5364(24)60554-6.

[45] Zhu H, Wang K, Yang L, et al. Yanghe Pingchuan Granule promotes BMSCs homing in asthmatic rats by upregulating miR-139-5p and downregulating Notch1/Hes1 pathway. J South Med Univ‌. 2020; 40(12):1703-1711.

[46] Turan RD, Albayrak E, Uslu M, et al. Development of small molecule MEIS inhibitors that modulate HSC activity. Sci Rep. 2020;10:7994. https://doi.org/10.1038/s41598-020-64888-3.

[47] Marquez-Curtis LA, Janowska-Wieczorek A. Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF-1/CXCR4 axis. BioMed Res Int. 2013;2013:561098. https://doi.org/10.1155/2013/561098.

[48] Ling K, Peng L, Feng Z, et al. Stromal derived factor-1/CXCR4 axis involved in bone marrow mesenchymal stem cells recruitment to injured liver. Stem Cells Int. 2016;2016:8906945. https://doi.org/10.1155/2016/8906945.

[49] Liu Y, Liu N, Li X, et al. Ginsenoside Rb 1 modulates the migration of bone-derived mesenchymal stem cells through the SDF-1/CXCR4 axis and PI3K/Akt pathway. Dis Markers. 2022;2022:5196682. https://doi.org/10.1155/2022/5196682.

[50] Gambaryan N, Perros F, Montani D, et al. Targeting of c-kit + haematopoietic progenitor cells prevents hypoxic pulmonary hypertension. Eur Respir J. 2011; 37(6):1392-1399. https://doi.org/10.1183/09031936.00045710.

[51] Peng H, Ye T, Deng L, et al. Sequential treatment with activin and hepatocyte growth factor induces FOXM1 to promote colorectal cancer liver metastasis. Can J Gastroenterol Hepatol. 2022;2022:8996203. https://doi.org/10.1155/2022/8996203.

[52] Xu M, Wei X, Fang J, et al. Combination of SDF-1 and bFGF promotes bone marrow stem cell-mediated periodontal ligament regeneration. Biosci Rep. 2019; 39(12):BSR20190785. https://doi.org/10.1042/bsr20190785.

[53] Yang J, Wang Y, Cai X, et al. Comparative pharmacokinetics and tissue distribution of polydatin, resveratrol, and emodin after oral administration of Huzhang and Huzhang-Guizhi herb-pair extracts to rats. J Ethnopharmacol. 2024;318:117010. https://doi.org/10.1016/j.jep.2023.117010.

[54] Chen C, Song C, Zhang D, et al. Effect of resveratrol combined with atorvastatin on re-endothelialization after drug-eluting stents implantation and the underlying mechanism. Life Sci. 2020;245:117349. https://doi.org/10.1016/j.lfs.2020.117349.