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Matrix Metalloproteinase 2 (MMP2) and MMP9 Secreted by Erythropoietin-Activated Endothelial Cells Promote Neural Progenitor Cell Migration
Open accessAbstract
We investigated the hypothesis that endothelial cells activated by erythropoietin (EPO) promote the migration of neuroblasts. This hypothesis is based on observations in vivo that treatment of focal cerebral ischemia with EPO enhances the migration of neuroblasts to the ischemic boundary, a site containing activated endothelial cells and angiogenic microvasculature. To model the microenvironment within the ischemic boundary zone, we used a coculture system of mouse brain endothelial cells (MBECs) and neural progenitor cells derived from the subventricular zone of the adult mouse. Treatment of MBECs with recombinant human EPO (rhEPO) significantly increased secretion of matrix metalloproteinase 2 (MMP2) and MMP9. rhEPO-treated MBEC supernatant as conditioned medium significantly increased the migration of neural progenitor cells. Application of an MMP inhibitor abolished the supernatant-enhanced migration. Incubation of neurospheres alone with rhEPO failed to increase progenitor cell migration. rhEPO activated phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and extracellular signal-regulated kinase (ERK1/2) in MBECs. Selective inhibition of the PI3K/Akt and ERK1/2 pathways significantly attenuated the rhEPO-induced MMP2 and MMP9, which suppressed neural progenitor cell migration promoted by the rhEPO-activated MBECs. Collectively, our data show that rhEPO-activated endothelial cells enhance neural progenitor cell migration by secreting MMP2 and MMP9 via the PI3K/Akt and ERK1/2 signaling pathways. These data demonstrate that activated endothelial cells can promote neural progenitor cell migration, and provide insight into the molecular mechanisms underlying the attraction of newly generated neurons to injured areas in brain.
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“In the peri-infarct tissue, newly formed vessels create a milieu for the migration, homing, and neuronal differentiation of neuroblasts via release of stromal derived factor 1, VEGF, and matrix metalloproteinases 2 and 9, which attract neuroblasts.58,59”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [58]
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“The interactions between endothelial cells and neuroblasts are especially strong during the first month after stroke.57,58”
From Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation (2012) · cites this paper as [58]
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Párraga-Viúdez, M. J., Sánchez-Gutiérrez, M., Quirós-Jiménez, A., Rangel-Zúñiga, O. A., López‐Miranda, J., Alcala-Diaz, J. F., & Delgado‐Lista, J. (2026) · Journal of Advanced Research · doi:10.1016/j.jare.2026.07.024
Metadata
- Authors
- Wang, L., Zhang, Z. G., Zhang, R. L., Gregg, S. R., Hozeska-Solgot, A., LeTourneau, Y., Wang, Y., & Chopp, M.
- Affiliations
- Henry Ford Health (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2006-05-31
- Volume
- 26
- Issue
- 22
- Pages
- 5996-6003
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6675216
- OpenAlex
- W2062253564
- Cited by
- 316
- References
- 49
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 7 · 2023: 8 · 2022: 5 · 2021: 15 · 2020: 14 · 2019: 14 · 2018: 10 · 2017: 16 · 2016: 13 · 2015: 26 · 2014: 20 · 2013: 16 · 2012: 26
- FWCI
- 7.24
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL064766, R01HL64766)
- National Institute of Neurological Disorders and Stroke (P01NS23393, P01NS023393, P01NS42345, R01NS043324, P01NS042345, R01 NS 43324)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Keywords
- erythropoietin, MMP-2, MMP-9, endothelial cells, focal cerebral ischemia, PI3K/Akt signaling, ERK signaling, subventricular zone, neurogenesis, angiogenesis, conditioned medium
- MeSH terms
- Animals, Cell Movement, Cerebrovascular Circulation, Endothelium, Vascular, Erythropoietin, Humans, Male, Neurons, Recombinant Proteins, Stem Cells, Rats, Wistar, Genes, Reporter, Coculture Techniques, Matrix Metalloproteinase 2, Matrix Metalloproteinase 9, Mice, Rats
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