{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T19:33:54Z","timestamp":1780083234097,"version":"3.54.0"},"reference-count":48,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T00:00:00Z","timestamp":1644451200000},"content-version":"vor","delay-in-days":40,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81774260"],"award-info":[{"award-number":["81774260"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Oxidative Medicine and Cellular Longevity"],"published-print":{"date-parts":[[2022,1]]},"abstract":"<jats:p>Sick sinus syndrome (SSS), a complex type of cardiac arrhythmia, is a major health threat to humans. Shenfu injection (SFI), a formula of traditional Chinese medicine (TCM), is effective in improving bradyarrhythmia. However, the underlying mechanism of SFI\u2019s therapeutic effect is subject to few systematic investigations. The purpose of the present research is to examine whether SFI can boost the differentiation effectiveness of bone marrow mesenchymal stem cells (BMSCs) into pacemaker\u2010like cells and whether the transplantation of these cells can improve the pacing function of the sinoatrial node (SAN) in a rabbit model of SSS. BMSCs from New Zealand rabbits were extracted, followed by incubation in vitro. The flow cytometry was utilized to identify the expression of CD29, CD44, CD90, and CD105 surface markers. The isolated BMSCs were treated with SFI, and the whole\u2010cell patch\u2010clamp method was performed to detect hyperpolarization\u2010the activated cyclic nucleotide\u2010gated potassium channel 4 (HCN4) channel current activation curve. The SSS rabbit model was established using the formaldehyde wet dressing method, and BMSCs treated with SFI were transplanted into the SAN of the SSS rabbit model. We detected changes in the body\u2010surface electrocardiogram and recorded dynamic heart rate measurements. Furthermore, transplanted SFI\u2010treated BMSCs were subjected to HE staining, TUNEL staining, qPCR, western blotting, immunofluorescence, immunohistochemistry, and enzyme\u2010linked immunosorbent assay to study their characteristics. Our results indicate that the transplantation of SFI\u2010treated BMSCs into the SAN of SSS rabbits improved the pacing function of the SAN. In vitro data showed that SFI induced the proliferation of BMSCs, promoted their differentiation capacity into pacemaker\u2010like cells, and increased the <jats:italic>HCN4<\/jats:italic> expression in BMSCs. In vivo, the transplantation of SFI treated\u2010BMSCs preserved the function of SAN in SSS rabbits, improved the expression of the <jats:italic>HCN4<\/jats:italic> gene and gap junction proteins (Cx43 and Cx45), and significantly upregulated the expression of cAMP in the SAN, compared to the SSS model group. In summary, the present research demonstrated that SFI might enhance the differentiation capacity of BMSCs into pacemaker\u2010like cells, hence offering a novel approach for the development of biological pacemakers. Additionally, we confirmed the effectiveness and safety of pacemaker\u2010like cells differentiated from BMSCs in improving the pacing function of the SAN.<\/jats:p>","DOI":"10.1155\/2022\/4299892","type":"journal-article","created":{"date-parts":[[2022,2,11]],"date-time":"2022-02-11T00:05:58Z","timestamp":1644537958000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Effect of Shenfu Injection on Differentiation of Bone Marrow Mesenchymal Stem Cells into Pacemaker\u2010Like Cells and Improvement of Pacing Function of Sinoatrial Node"],"prefix":"10.1155","volume":"2022","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7095-776X","authenticated-orcid":false,"given":"Qi","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Kang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zina","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingmin","family":"Chu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinhe","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijin","family":"Qing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9057-7326","authenticated-orcid":false,"given":"Xinjun","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2453-9273","authenticated-orcid":false,"given":"Rong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,2,10]]},"reference":[{"key":"e_1_2_9_1_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8159.2011.03150.x"},{"key":"e_1_2_9_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2007322118"},{"key":"e_1_2_9_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13287-020-01794-5"},{"key":"e_1_2_9_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2020.102043"},{"key":"e_1_2_9_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12015-021-10244-5"},{"key":"e_1_2_9_6_2","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/3621314"},{"key":"e_1_2_9_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2007.07.009"},{"key":"e_1_2_9_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/pace.12154"},{"key":"e_1_2_9_9_2","article-title":"The effect of astragaloside on pacemaker current and the cytoskeleton in rabbit sinoatrial node cells under the ischemia and reperfusion condition","volume":"9","author":"Liu R.","year":"2018","journal-title":"Frontiers in Pharmacology"},{"key":"e_1_2_9_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2017.02.006"},{"key":"e_1_2_9_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2007.02.006"},{"key":"e_1_2_9_12_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1010122108"},{"key":"e_1_2_9_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2008.3"},{"key":"e_1_2_9_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2018.12.040"},{"key":"e_1_2_9_15_2","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/9297163"},{"key":"e_1_2_9_16_2","doi-asserted-by":"publisher","DOI":"10.1538\/expanim.16-0121"},{"key":"e_1_2_9_17_2","article-title":"Effects of Shenfu injection and its main components on the contraction of isolated rat thoracic aortic rings","volume":"8","author":"Zhu J.","year":"2013","journal-title":"PLoS One"},{"key":"e_1_2_9_18_2","article-title":"Synergistic effect of Aconiti Lateralis Radix Praeparata water-soluble alkaloids and ginseng radix et rhizoma total ginsenosides compatibility on acute heart failure rats","volume":"1137","author":"Liu M.","year":"2020","journal-title":"Journal of Chromatography. 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