{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T11:25:35Z","timestamp":1782818735466,"version":"3.54.5"},"reference-count":101,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,7]],"date-time":"2024-01-07T00:00:00Z","timestamp":1704585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["16K11643"],"award-info":[{"award-number":["16K11643"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["K21K099290"],"award-info":[{"award-number":["K21K099290"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Cooperative Research Project Program of the Joint Usage\/Research Center at the Institute of Development, Aging, and Cancer, Tohoku University","award":["16K11643"],"award-info":[{"award-number":["16K11643"]}]},{"name":"Cooperative Research Project Program of the Joint Usage\/Research Center at the Institute of Development, Aging, and Cancer, Tohoku University","award":["K21K099290"],"award-info":[{"award-number":["K21K099290"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>PC12 cells, which are derived from rat adrenal pheochromocytoma cells, are widely used for the study of neuronal differentiation. NGF induces neuronal differentiation in PC12 cells by activating intracellular pathways via the TrkA receptor, which results in elongated neurites and neuron-like characteristics. Moreover, the differentiation requires both the ERK1\/2 and p38 MAPK pathways. In addition to NGF, BMPs can also induce neuronal differentiation in PC12 cells. BMPs are part of the TGF-\u03b2 cytokine superfamily and activate signaling pathways such as p38 MAPK and Smad. However, the brief lifespan of NGF and BMPs may limit their effectiveness in living organisms. Although PC12 cells are used to study the effects of various physical stimuli on neuronal differentiation, the development of new methods and an understanding of the molecular mechanisms are ongoing. In this comprehensive review, we discuss the induction of neuronal differentiation in PC12 cells without relying on NGF, which is already established for electrical, electromagnetic, and thermal stimulation but poses a challenge for mechanical, ultrasound, and light stimulation. Furthermore, the mechanisms underlying neuronal differentiation induced by physical stimuli remain largely unknown. Elucidating these mechanisms holds promise for developing new methods for neural regeneration and advancing neuroregenerative medical technologies using neural stem cells.<\/jats:p>","DOI":"10.3390\/ijms25020772","type":"journal-article","created":{"date-parts":[[2024,1,8]],"date-time":"2024-01-08T07:59:20Z","timestamp":1704700760000},"page":"772","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Physical Stimulation Methods Developed for In Vitro Neuronal Differentiation Studies of PC12 Cells: A Comprehensive Review"],"prefix":"10.3390","volume":"25","author":[{"given":"Kanako","family":"Tominami","sequence":"first","affiliation":[{"name":"Division of Oral Physiology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1666-9588","authenticated-orcid":false,"given":"Tada-aki","family":"Kudo","sequence":"additional","affiliation":[{"name":"Division of Oral Physiology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6187-6645","authenticated-orcid":false,"given":"Takuya","family":"Noguchi","sequence":"additional","affiliation":[{"name":"Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yohei","family":"Hayashi","sequence":"additional","affiliation":[{"name":"Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan"},{"name":"Graduate School of Life Sciences, Tohoku University, Sendai 980-8577, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4252-3638","authenticated-orcid":false,"given":"You-Ran","family":"Luo","sequence":"additional","affiliation":[{"name":"Division for Globalization Initiative, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takakuni","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Division for Globalization Initiative, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayumu","family":"Matsushita","sequence":"additional","affiliation":[{"name":"Division of Oral Physiology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Izumi","sequence":"additional","affiliation":[{"name":"Division of Oral Physiology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Sato","sequence":"additional","affiliation":[{"name":"Division of Pharmacology, Meikai University School of Dentistry, Sakado 350-0283, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Gengyo-Ando","sequence":"additional","affiliation":[{"name":"Division of Oral Physiology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8303-3905","authenticated-orcid":false,"given":"Atsushi","family":"Matsuzawa","sequence":"additional","affiliation":[{"name":"Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6620-1302","authenticated-orcid":false,"given":"Guang","family":"Hong","sequence":"additional","affiliation":[{"name":"Division for Globalization Initiative, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichi","family":"Nakai","sequence":"additional","affiliation":[{"name":"Division of Oral Physiology, Tohoku University Graduate School of Dentistry, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2424","DOI":"10.1073\/pnas.73.7.2424","article-title":"Establishment of a Noradrenergic Clonal Line of Rat Adrenal Pheochromocytoma Cells Which Respond to Nerve Growth Factor","volume":"73","author":"Greene","year":"1976","journal-title":"Proc. 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