{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T05:15:48Z","timestamp":1788412548682,"version":"build-2803163510"},"reference-count":44,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T00:00:00Z","timestamp":1788048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171387"],"award-info":[{"award-number":["82171387"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82171387"],"award-info":[{"award-number":["82171387"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Brain Sci.","Brain Sciences"],"abstract":"<jats:p>Background\/Objectives: Ischemic stroke (IS) induces substantial phenotypic remodeling within the neurovascular unit, and pericytes have been implicated in the cellular responses to ischemic injury. However, the molecular characteristics and regulatory mechanisms underlying pericyte phenotypic remodeling after ischemic stroke remain incompletely understood. Methods: In this study, we used PDGFR-\u03b2-CreERT2; ZsGreen lineage-tracing mice and a middle cerebral artery occlusion (MCAO) model to characterize the temporal changes in PDGFR-\u03b2-lineage cells following ischemic injury. In vitro, human brain vascular pericytes (HBVPs) exposed to oxygen\u2013glucose deprivation\/reperfusion (OGD\/R) and subsequently maintained in neurobasal medium to examine ischemia-related phenotypic changes. The involvement of KLF2-associated signaling was further investigated using KLF2 knockdown approaches. Results: We observed increased expression of Nestin in PDGFR-\u03b2-lineage cells during the early post-ischemic period, followed by the emergence of subsets co-expressing GFAP or DCX during the subacute stage. These findings indicate the acquisition of neuroglial- and neuronal-associated molecular features, rather than providing definitive evidence of lineage conversion or functional differentiation. The expression of these markers declined at later stages, whereas PDGFR-\u03b2-lineage cells were also associated with vascular remodeling during the recovery phase. In vitro, OGD\/R-treated HBVPs exhibited increased expression of DCX, MAP2, and NeuN. KLF2 knockdown attenuated these molecular changes. Consistently, OGD\/R was associated with increased KLF2, phosphorylated ERK1\/2, and MAP2 expression, whereas KLF2 knockdown reduced ERK1\/2 phosphorylation and MAP2 expression. These findings suggest that KLF2 is associated with ERK1\/2 activation and MAP2 expression during ischemia-related phenotypic remodeling of PDGFR-\u03b2-lineage cells. Conclusions: Overall, our results identify transient neuroglial- and neuronal-associated molecular changes in pericytes after ischemic injury and provide evidence for an association between KLF2 and ERK1\/2\u2013MAP2 signaling in this process, while further studies are required to determine whether these changes represent stable lineage conversion or functional neuronal differentiation.<\/jats:p>","DOI":"10.3390\/brainsci16090924","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T12:41:18Z","timestamp":1788266478000},"page":"924","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["KLF2 Is Associated with ERK1\/2\u2013MAP2 Activation and Neuron-like Phenotypic Remodeling of PDGFR-\u03b2-Lineage Cells Following Ischemic Stroke"],"prefix":"10.3390","volume":"16","author":[{"given":"Qiulu","family":"Liu","sequence":"first","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200070, China"},{"name":"Stem Cell Research Center, School of Medicine, Tongji University, Shanghai 200070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sutong","family":"Xu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200070, China"},{"name":"Stem Cell Research Center, School of Medicine, Tongji University, Shanghai 200070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200070, China"},{"name":"Stem Cell Research Center, School of Medicine, Tongji University, Shanghai 200070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengyu","family":"Lv","sequence":"additional","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200070, China"},{"name":"Stem Cell Research Center, School of Medicine, Tongji University, Shanghai 200070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenming","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200070, China"},{"name":"Stem Cell Research Center, School of Medicine, Tongji University, Shanghai 200070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yali","family":"Wang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200070, China"},{"name":"Stem Cell Research Center, School of Medicine, Tongji University, Shanghai 200070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyue","family":"Zhou","sequence":"additional","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200070, China"},{"name":"Stem Cell Research Center, School of Medicine, Tongji University, Shanghai 200070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuping","family":"Luo","sequence":"additional","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200070, China"},{"name":"Stem Cell Research Center, School of Medicine, Tongji University, Shanghai 200070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siguang","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital, School of Medicine, Tongji University, Shanghai 200070, China"},{"name":"Stem Cell Research Center, School of Medicine, Tongji University, Shanghai 200070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,30]]},"reference":[{"key":"ref_1","unstructured":"GBD 2019 Stroke Collaborators (2021). Global, regional, and national burden of stroke and its risk factors, 1990\u20132019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol., 20, 795\u2013820."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s00401-022-02452-1","article-title":"Profiling the neurovascular unit unveils detrimental effects of osteopontin on the blood-brain barrier in acute ischemic stroke","volume":"144","author":"Spitzer","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Liu, Q., and Zhang, X. (2023). Multimodality neuroimaging in vascular mild cognitive impairment: A narrative review of current evidence. Front. Aging Neurosci., 15.","DOI":"10.3389\/fnagi.2023.1073039"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1111\/cns.13561","article-title":"Neurovascular Unit: A critical role in ischemic stroke","volume":"27","author":"Wang","year":"2021","journal-title":"CNS Neurosci. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.1177\/0271678X20911331","article-title":"Multifaceted roles of pericytes in central nervous system homeostasis and disease","volume":"40","author":"Zheng","year":"2020","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.4103\/NRR.NRR-D-24-01472","article-title":"Pericyte-glial cell interactions: Insights into brain health and disease","volume":"21","author":"Sepehrinezhad","year":"2026","journal-title":"Neural Regen. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e141","DOI":"10.1161\/CIRCRESAHA.121.319288","article-title":"Heart and Brain Pericytes Exhibit a Pro-Fibrotic Response After Vascular Injury","volume":"129","author":"Pham","year":"2021","journal-title":"Circ. Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Li, P., and Fan, H. (2023). Pericyte Loss in Diseases. Cells, 12.","DOI":"10.3390\/cells12151931"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Sato, Y., Falcone-Juengert, J., Tominaga, T., Su, H., and Liu, J. (2022). Remodeling of the Neurovascular Unit Following Cerebral Ischemia and Hemorrhage. Cells, 11.","DOI":"10.3390\/cells11182823"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1038\/nn.4288","article-title":"Pericytes of the neurovascular unit: Key functions and signaling pathways","volume":"19","author":"Sweeney","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Nishiyama, R., Nakagomi, T., Nakano-Doi, A., Kuramoto, Y., Tsuji, M., and Yoshimura, S. (2024). Neonatal Brains Exhibit Higher Neural Reparative Activities than Adult Brains in a Mouse Model of Ischemic Stroke. Cells, 13.","DOI":"10.3390\/cells13060519"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1016\/j.stem.2012.07.007","article-title":"Reprogramming of pericyte-derived cells of the adult human brain into induced neuronal cells","volume":"11","author":"Karow","year":"2012","journal-title":"Cell Stem Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/j.stem.2016.12.006","article-title":"Pericytes of Multiple Organs Do Not Behave as Mesenchymal Stem Cells In Vivo","volume":"20","author":"Cattaneo","year":"2017","journal-title":"Cell Stem Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1161\/ATVBAHA.125.322700","article-title":"ANGPTL4 Prevents Atherosclerosis by Preserving KLF2 to Suppress EndMT and Mitigates Endothelial Dysfunction","volume":"45","author":"Cho","year":"2025","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Wittner, J., and Schuh, W. (2021). Kr\u00fcppel-like Factor 2 (KLF2) in Immune Cell Migration. Vaccines, 9.","DOI":"10.3390\/vaccines9101171"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1089\/ars.2010.3647","article-title":"\u201cGo with the flow\u201d: How Kr\u00fcppel-like factor 2 regulates the vasoprotective effects of shear stress","volume":"15","author":"Nayak","year":"2011","journal-title":"Antioxid. Redox Signal"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1686","DOI":"10.1161\/01.RES.0000267856.00713.0a","article-title":"Role of Kr\u00fcppel-like transcription factors in endothelial biology","volume":"100","author":"Atkins","year":"2007","journal-title":"Circ. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1055\/s-0037-1616937","article-title":"Key transcriptional regulators of the vasoprotective effects of shear stress","volume":"29","author":"Boon","year":"2009","journal-title":"Hamostaseologie"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e2403818","DOI":"10.1002\/advs.202403818","article-title":"CircFndc3b Mediates Exercise-Induced Neuroprotection by Mitigating Microglial\/Macrophage Pyroptosis via the ENO1\/KLF2 Axis in Stroke Mice","volume":"12","author":"Zhao","year":"2025","journal-title":"Adv. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1498","DOI":"10.1161\/CIRCRESAHA.125.326391","article-title":"Endothelial SRSF1 Promotes Ischemia-Induced Angiogenesis via ATF3-KLF2-S1PR1 Pathway","volume":"137","author":"Zhu","year":"2025","journal-title":"Circ. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2327","DOI":"10.4103\/NRR.NRR-D-23-01758","article-title":"Kr\u00fcppel-like factor 2 (KLF2), a potential target for neuroregeneration","volume":"19","author":"Hansda","year":"2024","journal-title":"Neural Regen. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.neubiorev.2021.10.009","article-title":"ERK\/MAPK signalling in the developing brain: Perturbations and consequences","volume":"131","author":"Iroegbu","year":"2021","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1126\/science.1072682","article-title":"Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases","volume":"298","author":"Johnson","year":"2002","journal-title":"Science"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1038\/s41420-022-00888-8","article-title":"Targeting the Erk1\/2 and autophagy signaling easily improved the neurobalst differentiation and cognitive function after young transient forebrain ischemia compared to old gerbils","volume":"8","author":"Wang","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kurtzeborn, K., Kwon, H.N., and Kuure, S. (2019). MAPK\/ERK Signaling in Regulation of Renal Differentiation. Int. J. Mol. Sci., 20.","DOI":"10.20944\/preprints201903.0138.v1"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Chan, W.S., Sideris, A., Sutachan, J.J., Montoya, G.J., Blanck, T.J., and Recio-Pinto, E. (2013). Differential regulation of proliferation and neuronal differentiation in adult rat spinal cord neural stem\/progenitors by ERK1\/2, Akt, and PLC\u03b3. Front. Mol. Neurosci., 6.","DOI":"10.3389\/fnmol.2013.00023"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1002\/glia.24361","article-title":"Vascular endothelial growth factor promotes transdifferentiation of astrocytes into neurons via activation of the MAPK\/Erk-Pax6 signal pathway","volume":"71","author":"Lei","year":"2023","journal-title":"Glia"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1501","DOI":"10.1177\/0271678X18769515","article-title":"PDGFR-\u03b2 restores blood-brain barrier functions in a mouse model of focal cerebral ischemia","volume":"39","author":"Shen","year":"2019","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.devcel.2011.07.001","article-title":"Pericytes: Developmental, physiological, and pathological perspectives, problems, and promises","volume":"21","author":"Armulik","year":"2011","journal-title":"Dev. Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1186\/s12974-026-03749-8","article-title":"Spatiotemporal dynamics of brain pericytes in ischemic stroke","volume":"23","author":"Zhong","year":"2026","journal-title":"J. Neuroinflammation"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Fu, J., Liang, H., Yuan, P., Wei, Z., and Zhong, P. (2023). Brain pericyte biology: From physiopathological mechanisms to potential therapeutic applications in ischemic stroke. Front. Cell Neurosci., 17.","DOI":"10.3389\/fncel.2023.1267785"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.5551\/jat.RV22007","article-title":"Pericyte-Mediated Molecular Mechanisms Underlying Tissue Repair and Functional Recovery after Ischemic Stroke","volume":"30","author":"Nakamura","year":"2023","journal-title":"J. Atheroscler. Thromb."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"6110","DOI":"10.7150\/thno.97165","article-title":"Single-cell profiling of brain pericyte heterogeneity following ischemic stroke unveils distinct pericyte subtype-targeted neural reprogramming potential and its underlying mechanisms","volume":"14","author":"Loan","year":"2024","journal-title":"Theranostics"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Cao, L., Zhou, Y., Chen, M., Li, L., and Zhang, W. (2021). Pericytes for Therapeutic Approaches to Ischemic Stroke. Front. Neurosci., 15.","DOI":"10.3389\/fnins.2021.629297"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s12974-016-0523-9","article-title":"Brain pericytes serve as microglia-generating multipotent vascular stem cells following ischemic stroke","volume":"13","author":"Sakuma","year":"2016","journal-title":"J. Neuroinflammation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.1002\/stem.1977","article-title":"Brain vascular pericytes following ischemia have multipotential stem cell activity to differentiate into neural and vascular lineage cells","volume":"33","author":"Nakagomi","year":"2015","journal-title":"Stem Cells"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"H796","DOI":"10.1152\/ajpheart.00712.2012","article-title":"Kruppel-like factor 2 protects against ischemic stroke by regulating endothelial blood brain barrier function","volume":"304","author":"Shi","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2796","DOI":"10.1007\/s12015-025-10968-8","article-title":"Engineering the Future of Stem Cells in Vascular Reconstruction: A Leap Towards Functional Endothelialized Tissue-Engineered Vascular Conduits","volume":"21","author":"Oubari","year":"2025","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e007566","DOI":"10.1161\/JAHA.117.007566","article-title":"Uremic Advanced Glycation End Products and Protein-Bound Solutes Induce Endothelial Dysfunction Through Suppression of Kr\u00fcppel-Like Factor 2","volume":"7","author":"Saum","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.devcel.2014.12.016","article-title":"Regulation of \u03b21 integrin-Klf2-mediated angiogenesis by CCM proteins","volume":"32","author":"Renz","year":"2015","journal-title":"Dev. Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1161\/01.ATV.0000256466.65450.ce","article-title":"KLF2 suppresses TGF-beta signaling in endothelium through induction of Smad7 and inhibition of AP-1","volume":"27","author":"Boon","year":"2007","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41420-022-00813-z","article-title":"KLF2 up-regulates IRF4\/HDAC7 to protect neonatal rats from hypoxic-ischemic brain damage","volume":"8","author":"Wu","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Lyu, J., DeMarco, A.G., Sweet, R.A., and Grubisha, M.J. (2025). MAP2 phosphorylation: Mechanisms, functional consequences, and emerging insights. Front. Cell Neurosci., 19.","DOI":"10.3389\/fncel.2025.1610371"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"100052","DOI":"10.1016\/j.pharmr.2025.100052","article-title":"The microcirculation, the blood-brain barrier, and the neurovascular unit in health and Alzheimer disease: The aberrant pericyte is a central player","volume":"77","author":"Divecha","year":"2025","journal-title":"Pharmacol. Rev."}],"container-title":["Brain Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/9\/924\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T04:28:25Z","timestamp":1788409705000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3425\/16\/9\/924"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,30]]},"references-count":44,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["brainsci16090924"],"URL":"https:\/\/doi.org\/10.3390\/brainsci16090924","relation":{},"ISSN":["2076-3425"],"issn-type":[{"value":"2076-3425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,30]]}}}