Bone marrow stromal cells upregulate expression of bone morphogenetic proteins 2 and 4, gap junction protein connexin-43 and synaptophysin after stroke in rats.
Bone morphogenetic proteins play a key role in astrocytic differentiation. Astrocytes express the gap junctional protein connexin-43, which permits exchange of small molecules in brain and enhances synaptic efficacy. Bone marrow stromal cells produce soluble factors including bone morphogenetic protein 2 and bone morphogenetic protein 4 (bone morphogenetic protein 2/4) in ischemic brain. Here, we tested whether intra-carotid infusion of bone marrow stromal cells promotes synaptophysin expression and neurological functional recovery after stroke in rats. Adult male Wistar rats were subjected to 2 h of right middle cerebral artery occlusion. Rats were treated with or without bone marrow stromal cells at 24 h after middle cerebral artery occlusion via intra-arterial injection (n=8/group). A battery of functional tests was performed. Immunostaining of 5-bromo-2-deoxyuridine, Ki67, bone morphogenetic protein 2/4, connexin-43, synaptophysin, glial fibrillary acidic protein, neuronal nuclear antigen, and double staining of 5-bromo-2-deoxyuridine/glial fibrillary acidic protein, 5-bromo-2-deoxyuridine/neuronal nuclear antigen, glial fibrillary acidic protein/bone morphogenetic protein 2/4 and glial fibrillary acidic protein/connexin-43 were employed. Rats treated with bone marrow stromal cells significantly (P<0.05) improved functional recovery compared with the controls. 5-Bromo-2-deoxyuridine and Ki67 positive cells in the ipsilateral subventricular zone were significantly (P<0.05) increased in bone marrow stromal cell treatment group compared with the controls, respectively. Administration of bone marrow stromal cells significantly (P<0.05) promoted the proliferating cell astrocytic differentiation, and increased bone morphogenetic protein 2/4, connexin-43 and synaptophysin expression in the ischemic boundary zone compared with the controls, respectively. Bone morphogenetic protein 2/4 expression correlated with the expression of connexin-43 (r=0.84, P<0.05) and connexin-43 expression correlated with the expression of synaptophysin (r=0.73, P<0.05) in the ischemic boundary zone, respectively. Administration of bone marrow stromal cells via an intra-carotid route increases endogenous brain bone morphogenetic protein 2/4 and connexin-43 expression in astrocytes and promotes synaptophysin expression, which may benefit functional recovery after stroke in rats.
Zhang
C
C
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
Li
Y
Y
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
Chen
J
J
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
Gao
Q
Q
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
Zacharek
A
A
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA.
Kapke
A
A
Department of Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit, MI 48202, USA.
Chopp
M
M
Department of Neurology, Henry Ford Health System, Detroit, MI 48202, USA; Department of Physics, Oakland University, Rochester, MI 48309, USA. Electronic address: chopp@neuro.hfh.edu.
D000704:Analysis of Variance; D000818:Animals; D001835:Body Weight / Q000502:physiology; D001854:Bone Marrow Cells / Q000502:physiology*; D016026:Bone Marrow Transplantation / Q000379:methods; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D018031:Connexin 43 / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D007269:Injections, Intra-Arterial / Q000379:methods; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017154:Stromal Cells / Q000502:physiology* / Q000637:transplantation; D016708:Synaptophysin / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
C525720:Bmp2 protein, rat; C525811:Bmp4 protein, rat; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D018031:Connexin 43; D005904:Glial Fibrillary Acidic Protein; D019394:Ki-67 Antigen; D016708:Synaptophysin; D016212:Transforming Growth Factor beta; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine