Transplantation of RADA16-BDNF peptide scaffold with human umbilical cord mesenchymal stem cells forced with CXCR4 and activated astrocytes for repair of traumatic brain injury.
Due to the poor self-regeneration of brain tissue, stem cell transplantation therapy is purported to enable the replacement of lost neurons after traumatic brain injury (TBI). The main challenge of brain regeneration is whether the transplanted cells can survive and carry out neuronal functions in the lesion area. The brain is a complex neuronal network consisting of various types of cells that significantly influence on each other, and the survival of the implanted stem cells in brain is critically influenced by the surrounding cells. Although stem cell-based therapy is developing rapidly, most previous studies just focus on apply single type of stem cells as cell source. Here, we found that co-culturing human umbilical cord mesenchymal stem cells (hUC-MSCs) directly with the activated astrocytes benefited to the proliferation and neuron differentiation of hUC-MSCs in vitro. In this study, hUC-MSCs and the activated astrocytes were seeded in RADA16-BDNF peptide scaffold (R-B-SPH scaffold), a specifical self-assembling peptide hydrogel, in which the environment promoted the differentiation of typical neuron-like cells with neurites extending in three-dimensional directions. Moreover, the results showed co-culture of hUC-MSCs and activated astrocytes promoted more BDNF secretion which may benefit to both neural differentiation of ectogenic hUC-MSCs and endogenic neurogenesis. In order to promote migration of the transplanted hUC-MSCs to the host brain, the hUC-MSCs were forced with CXC chemokine receptor 4 (CXCR4). We found that the moderate-sized lesion cavity, but not the large cavity caused by TBI was repaired via the transplantation of hUC-MSCsCXCR4and activated astrocytes embedded in R-B-SPH scaffolds. The functional neural repair for TBI demonstrated in this study is mainly due to the transplantation system of double cells, hUC-MSCs and activated astrocytes. We believe that this novel cell transplantation system offers a promising treatment option for cell replacement therapy for TBI.



In this reach, we specifically linked RGIDKRHWNSQ, a functional peptide derived from BDNF, to the C-terminal of RADARADARADARADA (RADA16) to structure a functional self-assembling peptide hydrogel scaffold, RADA16-BDNF (R-B-SPH scaffold) for the better transplantation of the double cell unit. Also, the novel scaffold was used as cell-carrier for transplantation double cell unit (hUC-MSCs/astrocyte) for treating traumatic brain injury. The results of this study showing that R-B-SPH scaffold was pliancy and flexibility to fit the brain lesion cavity and promotes the outgrowth of axons and dendrites of the neurons derived from hUC-MSCs in vitro and in vivo, indicating the 3D R-B-SPH scaffold provided a suitable microenvironment for hUC-MSC survival, proliferation and differentiation. Also, our results showing the double-cells transplantation system (hUC-MSCs/astrocyte) may be a novel cell-based therapeutic strategy for neuroregeneration after TBI with potential value for clinical application.
Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong 226001, China; Department of Neurosurgery, Xinhua Hospital of Kazak Autonomous Prefecture of Ili, Sinkiang 835000, China; Department of Laboratory of Surgery, Affiliated Hospital of Nantong University, Nantong 226001, China.
W
W
Shi
Department of Neurosurgery, The First People's Hospital of Wujiang, Soochow 215200, China; Department of Laboratory of Surgery, Affiliated Hospital of Nantong University, Nantong 226001, China.
C J
CJ
Huang
Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong 226001, China.
X D
XD
Xu
Department of Anatomy and Neurobiology, School of Medicine, Nantong University, Nantong 226001, China.
G H
GH
Jin
Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
R Q
RQ
Huang
Department of Pathology and Clinical Biobank, Affiliated Hospital of Nantong University, Nantong 226001, China.
J F
JF
Huang
Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong 226001, China.
Y N
YN
Chen
Department of Laboratory of Surgery, Affiliated Hospital of Nantong University, Nantong 226001, China.
S Q
SQ
Ju
Center of Analysis and Measurement, Fudan University, Shanghai 200433, China.
Y
Y
Wang
Jiangsu Key Laboratory of Neuroregeneration, Nantong University, Nantong 226001, China.
Y W
YW
Shi
Department of Anatomy and Neurobiology, School of Medicine, Nantong University, Nantong 226001, China.
J B
JB
Qin
Department of Obstetrics and Gynecology, Affiliated Hospital of Nantong University, Nantong 226001, China.
Y Q
YQ
Zhang
Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong 226001, China.
Q Q
QQ
Liu
Medical Image Center, Affiliated Hospital of Nantong University, Nantong 226001, China.
X B
XB
Wang
Department of Anatomy and Neurobiology, School of Medicine, Nantong University, Nantong 226001, China. Electronic address: zhangxinhua@ntu.edu.cn.
X H
XH
Zhang
Department of Neurosurgery, Affiliated Hospital of Nantong University, Nantong 226001, China. Electronic address: ntfychenjian@126.com.
J
J
Chen
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D000070642:Brain Injuries, Traumatic / Q000473:pathology / Q000628:therapy*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D018920:Coculture Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000378:metabolism*; D012038:Regeneration / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D054457:Tissue Scaffolds / Q000737:chemistry*; D014470:Umbilical Cord / Q000166:cytology
D019208:Brain-Derived Neurotrophic Factor; D054377:Chemokine CXCL12; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010455:Peptides; C546681:RADA16-I; D019718:Receptors, CXCR4
Astrocytes; CXCR4/SDF-1axis; Neuronal differentiation; Peptide hydrogel; Transplantation; Traumatic brain injury; hUC-MSCs