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Monocistronic expression of four transcription factors (\n                    <jats:italic>CRX<\/jats:italic>\n                    ,\n                    <jats:italic>NEUROD<\/jats:italic>\n                    ,\n                    <jats:italic>RAX<\/jats:italic>\n                    , and\n                    <jats:italic>OTX2<\/jats:italic>\n                    ) has been demonstrated to induce the expression of phototransduction-associated genes and confer light responsiveness in fibroblasts. In contrast, polycistronic expression of the same four factors resulted in the upregulation of only two cone-specific genes, indicating that optimization of reprogramming conditions is required to achieve complete photoreceptor differentiation. In this study, we focused on M\u00fcller glial cells, which exhibit regenerative potential in the retina of lower vertebrates, and explored their reprogramming into photoreceptor-like cells. We thus combined polycistronic expression of the aforementioned transcription factors and a pharmacological reprogramming approach utilizing a defined cocktail of small molecules. Transcriptomic analysis revealed that transcription factor introduction alone led to the upregulation of the genes related to neuronal identity and extracellular matrix components. Notably, the combination of transcription factor expression and chemical treatment induced photoreceptor-specific gene expression. However, no genes associated with phototransduction were detected, suggesting that further refinement is required to promote full differentiation into functionally mature light-responsive photoreceptors. Overall, our findings demonstrate that immortalized M\u00fcller glia can partially activate neuronal and photoreceptor genes through reprogramming, suggesting their potential for scalable drug screening and disease modeling. Clinical trial number: not applicable.\n                  <\/jats:p>","DOI":"10.1007\/s11626-026-01164-0","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T14:28:38Z","timestamp":1772029718000},"page":"685-703","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Direct reprogramming of M\u00fcller glia into photoreceptors via multiple transcription factors and small molecules: molecular mechanisms and transcriptomic analysis"],"prefix":"10.1007","volume":"62","author":[{"given":"Yuka","family":"Endo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eriko","family":"Sugano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Seko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomokazu","family":"Fukuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kitako","family":"Tabata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taira","family":"Kakizaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Maruoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takanori","family":"Yokoyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanaho","family":"Mori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taku","family":"Ozaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanlan","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1051-2301","authenticated-orcid":false,"given":"Hiroshi","family":"Tomita","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,25]]},"reference":[{"key":"1164_CR1","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1016\/j.surg.2008.08.027","volume":"144","author":"JT Adler","year":"2008","unstructured":"Adler JT, Hottinger DG, Kunnimalaiyaan M, Chen H (2008) Histone deacetylase inhibitors upregulate Notch-1 and inhibit growth in pheochromocytoma cells. 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