BMP4 inhibits myogenic differentiation of bone marrow-derived mesenchymal stromal cells in mdx mice.
OBJECTIVE
Bone marrow-derived mesenchymal stromal cells (BMSCs) are a promising therapeutic option for treating Duchenne muscular dystrophy (DMD). Myogenic differentiation occurs in the skeletal muscle of the mdx mouse (a mouse model of DMD) after BMSC transplantation. The transcription factor bone morphogenic protein 4 (BMP4) plays a crucial role in growth regulation, differentiation and survival of many cell types, including BMSCs. We treated BMSCs with BMP4 or the BMP antagonist noggin to examine the effects of BMP signaling on the myogenic potential of BMSCs in mdx mice.


METHODS
We added BMP4 or noggin to cultured BMSCs under myogenic differentiation conditions. We then injected BMP4- or noggin-treated BMSCs into the muscles of mdx mice to determine their myogenic potential.


RESULTS
We found that the expression levels of desmin and myosin heavy chain decreased after treating BMSCs with BMP4, whereas the expression levels of phosphorylated Smad, a downstream target of BMP4, were higher in these BMSCs than in the controls. Mdx mouse muscles injected with BMSCs pretreated with BMP4 showed decreased dystrophin expression and increased phosphorylated Smad levels compared with muscles injected with non-treated BMSCs. The opposite effects were seen after pretreatment with noggin, as expected.


CONCLUSIONS
Our results identified BMP/Smad signaling as an essential negative regulator of promyogenic BMSC activity; inhibition of this pathway improved the efficiency of BMSC myogenic differentiation, which suggests that this pathway might serve as a target to regulate BMSC function for better myogenic differentiation during treatment of DMD and degenerative skeletal muscle diseases.
Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Key Laboratory for the Diagnosis and Treatment of Major Neurological Disease, Guangzhou, China.
Cao
C
Jiqing
Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Key Laboratory for the Diagnosis and Treatment of Major Neurological Disease, Guangzhou, China.
Li
L
Yaqin
Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Key Laboratory for the Diagnosis and Treatment of Major Neurological Disease, Guangzhou, China.
Liang
L
Yingyin
Department of Institute of Gynecology and Obstetrics, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Chen
C
Fei
Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Key Laboratory for the Diagnosis and Treatment of Major Neurological Disease, Guangzhou, China.
Zhang
Z
Huili
Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Key Laboratory for the Diagnosis and Treatment of Major Neurological Disease, Guangzhou, China.
Zhu
Z
Yuling
Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, China.
Yang
Y
Juan
Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Feng
F
Shanwei
Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Key Laboratory for the Diagnosis and Treatment of Major Neurological Disease, Guangzhou, China. Electronic address: chengzhang100@hotmail.com.
Zhang
Z
Cheng
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D055415:Bone Morphogenetic Protein 4 / Q000494:pharmacology*; D002352:Carrier Proteins / Q000494:pharmacology*; D002454:Cell Differentiation; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D003893:Desmin / Q000096:biosynthesis; D004195:Disease Models, Animal; D016189:Dystrophin / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology; D051379:Mice; D018101:Mice, Inbred mdx; D024510:Muscle Development / Q000187:drug effects*; D018482:Muscle, Skeletal / Q000166:cytology; D020388:Muscular Dystrophy, Duchenne / Q000628:therapy; D018995:Myosin Heavy Chains / Q000096:biosynthesis; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000096:biosynthesis / Q000378:metabolism; D000099176:Noggin Protein
D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D003893:Desmin; D016189:Dystrophin; D018995:Myosin Heavy Chains; D051785:Smad Proteins; D000099176:Noggin Protein; C525810:Bmp4 protein, mouse
BMPs; BMSCs; Duchenne muscular dystrophy; Smad; dystrophin; mdx mice; myogenic differentiation