Due to the heterogeneous nature of pathophysiology of CP, standard medical procedures have different treatment outcomes. More recently, autologous cellular therapy has evolved as a strategy for treatment of cerebral palsy [20]. During childhood, brain neuroplasticity is at its maximum, making cell therapy a powerful treatment modality in children [21,22,23]. Various experimental studies have shown that cell transplantation in CP models can lead to survival of neurons, and differentiation of cells into neurons, oligodendrocytes and astrocytes [24,25]. Stem cells stimulate the recovery process by affecting damaged brain cells to regenerate via paracrine signaling [26]. Cell therapy can restore lost myelin by replacing dead oligodendrocytes and their precursor cells. Functional cell survival can be stimulated by introducing another type of cells that will be able to restore the lack of enzymes necessary for brain function [27]. Stem cells can reduce the levels of TNF, IL-1, IL-1 and IL-6 increased due to microglial activation [28]. These cells also secrete neurotropic and growth factors such as connective tissue growth factor, fibroblast growth factors, interleukins, vascular endothelial growth factor, fibroblast growth factor, and basic fibroblast growth factor, which are responsible for proliferation, cytoprotection, and angiogenesis, and stimulate recovery of lost tissue function [29,30]. During measurements, an increase in the number of CD90 positive cells was observed in each subsequent measurement. Mesenchymal cells increase angiogenesis by producing signaling molecules, stimulate tissue remodeling, decrease inflammation and activate the satellite cells. Moraes et al. [31] have hypothesized that CD90 controls the differentiation of MSCs by acting as a barrier in the pathway of differentiation commitment. Our data could indicate that the maintenance of MSC stemness and their paracrine effects rather than their differentiation underlie the good effects of therapy of our CP patients.
With the aim of studying safety, feasibility and efficacy of cell therapy in cerebral palsy syndrome, we present 24 cases with BMAC administration. Studies have shown that the entire bone marrow contains multiple stem cells: they represent a microenvironment around stem cells that enables cellular support and paracrine signaling by regulating also self-renewal and differentiation. Together with the niche, stem cells have better effect compared to single cell fractions [32,33]. BMAC contains different types of cells: platelets, erythrocytes, nucleated cells, progenitor cells, hematopoietic stem cells, mesenchymal stem cells. The aim is to bring hematopoiesis and mesenchymal and progenitor cells to the site of treatment. These cells are injected into the subarachnoid space by intrathecal injection. The procedure is minimally invasive and safe, probably the most effective route of administration. Intracranial transplantation may be considered as a form of treatment, but it involves the risk of surgical damage. In animal models of cerebral ischemia, it has been observed that during intravenous administration, most stem cells have been found in all organs except the brain, such as the lung, spleen, kidney, and intestines [34]. The question arises as to the openness of the hematoencephalic barrier to structures such as the stem cell niche, which does not classify intravenous stem cell administration as necessary administration route for BMAC.
With cell therapy, all patients underwent neurorehabilitation as part of the protocol. Most of them had been in the rehabilitation process before the intervention, but they still had a high degree of residual neurodeficiency. Physical treatment accelerates stem cell mobilization, proliferation and neurogenesis by increasing oxygen flow to the brain [35]. Cell therapy, rehabilitation and neurorehabilitation work synergistically and can together enhance the positive effects of healing.
In CP, damage to the motor control centers in the brain causes increased motor tone, leading to muscle stiffness. We assessed the motor function of the patients before and after cell injection. GMFCS scores had remarkable changes 12 months after transplantation compared with baseline. According to the Ashworth scale, there was a significant reduction in spasticity and, accordingly, patients movements became more flexible and easier. In a report from Lebanon, 17 sequential patients with CP treated with intrathecal administration of BMMC. All patients had an uneventful post-injection course with 12 of the evaluable patients treated having a good response using the Gross motor function classification system [36]. Chahine et al. shows that about 73% of patients with CP may benefit from this treatment. The improvement ranges from 0 to 3 score levels averaging 1.3 points. There is also a good degree of cognitive, functional, and bladder and bowel control as well as improvement of the spasticity [36]. Zali et al. reported a significant improvement 6 months after cell transplantation versus baseline according to GMFM, GMFCS, FIMþFAM and Ashworth Scale [37].
After treatment, 83% our patients developed some relaxation of the extremities. In XCell-Center 66.4% of the 104 treated patients reported improvements [38]. Sharma et al. reported an 85% improvement among cerebral palsy cases, out of which 75% reported improvement in muscle tone and 50% in speech among other symptoms [6]. These improvements suggest that the combination of cell therapy and rehabilitation can lead to functional restoration that reduces disability in CP, thereby improving the quality of life of these patients.
The brain needs training to get the best out of its potential for appropriate functional reorganization. The goal of rehabilitation in CP is to develop coordination, increase flexibility, balance and co-ordination, manage spasticity and maximize independence. Sources, types, numbers of cells managed, frequency and time of transplantation are concerns which need attention imperatively. Exercise enhances the effect of injected stem cells by activating and proliferating the local stem cells, promoting muscle angiogenesis and release of cytokines and nerve growth factors. Stem cells have the capacity of repairing the underlying neural and muscular dysfunction through its neuroregenerative property. Increased enrolment of hematopoietic stem cells to peripheral blood is detected post exercise. The neurorehabilitation promotes and assists neural plasticity [39]. Neurorehabilitation increases angiogenesis and oxygen supply to the brain thereby improving the cognitive function. [40,41]. Exercise and neurorehabilitation has a synergistic effect for the profits of cell transplantation.
One of the major limitations of this study is that it was a non-randomized open-label study and did not have an adequate placebo control group to compare the results. There is also a disadvantage of a rehabilitation-only group that can substantiate the effect of individual intervention of an autologous stem cell transfer. Disadvantage is also short follow-up period, since longer follow-up period may lead to more accurate data on the effectiveness of the intervention. The results however, should be confirmed in large studies.
This study shows that autologous BMAC transfer in combination with rehabilitation is a safe procedure, easily feasible and to some extent effective for the patients condition. This can help reduce the degree of impairment within cerebral palsy syndrome and improve the patient's quality of life. The ability of cell migration and differentiation should be assessed by determining a safe tracking procedure.