Cerebral palsy (CP) is a group of diseases whose common feature are motor disorders, which is the most commonly physical disability in childhood. This disease is a global public health issue with an estimated prevalence of 2‰—4‰ and imposes a substantial health burden on many countries. The children with CP exhibit a complex set of dysfunctions, including behavioral disorders, disturbances in sensation and perception, epilepsy, mental retardation, neurological dysplasia, cerebral anesthesia, poor learning ability and language deficits accompanied by their whole lifetimes. Brain tissue in the course of the disease is irreversibly damaged, there are many causes of damage lead to CP, such as hypoxia, ischemia, infection, injury or congenital defects. CP as a incurable disease has brought enormous mental and economic burden to the patient's family and society.
Nowadays, many treatment strategies have been developed for CP, which include various surgeries on muscles, tendons, bone and nerves, medications, electrical stimulation, patterning, conductive education, orthoses. However, all of the treatment strategies only provide symptomatic relief and none of them are ideal. Therefore, research new efficient strategies to trement CP is in an urgent need.
In recent years, HUCMSCs have been proved promising in possible treatment of several diseases and conditions such as diabetes, certain diabetic wounds and brain damage associated with neonatal hypoxia, stroke, autism, acute liver failure, CP and Alzheimer’s. HUCMSCs are better in contrast to embryonic and fetal stem cells ethically noncontroversial, inexpensive and readily available source of cells. HUCMSCs are multipotent stem cells, which are easy to obtain materials, rich sources, primitive cells, differentiation ability and secretion of cytokines are strong, immunogenicity is relatively low, and also with no ethical problems and little exogenous pollution and characterized by the ability to differentiate into specific cell types. HUCMSCs are capable of forming many different cell types and it has also become one of the most important cell sources for scientists to study the treatment of CP .
The key molecules of Rho/ROCK signaling pathway include NogoA、NgR、RhoA、Rac-1、Cdc42. NogoA protein is an important membrane protein, which is mainly expressed in oligodendrocytes and neurons of the central nervous system. NogoA belongs to the reticular family, a member of the neurite outgrowth inhibitor (Nogo) family, which is the most important and strongest inhibitor of axon growth in the central nervous system. Binding of NogoA to specific receptor NgR can induce cone collapse, axon growth collapse and atrophy, inhibit axon regeneration, and play a negative regulatory role in central nerve injury. NogoA can cause nerve damage by activating Rho. In vivo experiments showed that blocking NogoA expression may result in an increasing in dendrite spine density. Rac1 is involved in axonal formation of nerve cells in vivo. Rac1GTPase is essential for axon formation during hippocampal neuron development and can stimulate axon growth expansion, axon guidance, dendrite growth and neuronal polarity of nerve cells. Many studies have shown that Rac1 silencing can reduce and improve neuronal oxidative stress injury, and abnormal Rac1 activity may lead to axonal contraction and neuronal death after ischemia-reperfusion in models. CDC42 can regulate microfilaments, mediate the formation of filamentous pseudopods, participate in vesicle transport, regulate axon and dendrite formation and synaptic plasticity[16, 17].
Many studies demonstrated that HUCMSCs could migrate to the sites of brain injury in CP rats, reduce functional deficits, protect against white matter injury . The main purpose of using stem cells treatment of cerebral palsy is to use their regenerative capacity to rebuild damaged brain tissue, which can differentiate into nervous system regeneration and inhibit neuroinflammation. However, the data on the effectiveness of HUCMSCs therapy in cerebral palsy are still insufficient. So we need continue to research more about the HUCMSCs therapy mechanism for CP. CP injury is inevitably accompanied by the regeneration and repair of neurons and axons. Nerve regeneration is noticed to play an important role in the CP treatment. The regeneration of central nervous system(CNS) is related to the existence of factors against regeneration in the microenvironment of CNS. However, the effect of NogoA/NgR/Rho pathway on the regulation of HUCMSCs activity in CP is rarely reported and the specific mechanism is still unclear .
We hypothesized that NogoA/NgR/Rho pathway is involved in when use the HUCMSCs to treat CP. The aim of our study is to explore the role of NogoA/NgR/Rho pathway in the nerve regeneration mechanisms of the HUCMSCs and evaluate its potency as a new target for treating CP or the injury and diseases of central nervous system.
To further validate the therapeutic mechanisms of the NogoA/NgR/Rho pathway, HUCMSCs were injected into rats with hypoxia/ischemia-induced CP. In this article, we explain the effect in rat with CP and NogoA/NgR/Rho pathway potential molecular mechanisms by analyzing these changes, including NogoA、NgR、RhoA、Rac-1、Cdc42 expression levels of related nerve regeneration genes. This in vivo study in the rat CP model may provide new treatment method for CP patient in future.