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Science, Technology and Medicine open access publisher.Publish, read and share novel research. Stem Cell Therapyfor Islet RegenerationPhuc Pham Van1[1] University of Science,Vietnam National University HCM city, Vietnam1.
Stem Cell Therapy for Cerebral Palsy – A Novel OptionAlok Sharma1, Hemangi Sane2, Nandini Gokulchandran1, Prerna Badhe1, Pooja Kulkarni2 and Amruta Paranjape3[1] Department of Medical Service and Clinical Research, Neurogen Brain and Spine Institute, Mumbai, India[2] Department of Research and Development, Neurogen Brain and Spine Institute, Mumbai, India[3] Department of Neurorehabilitation, Neurogen Brain and Spine Institute, Mumbai, India1. Bianco P, Riminucci M, Gronthos S, Robey PG, Bone marrow stromal stem cells: nature, biology, and potential applications.
Orozco L, Munar A, Soler R, Alberca M, Soler F, Huguet M, Sentis J, Sanchez A, Garcia-Sancho J. O Diabetes e uma doenca conhecida como assassina silencioso pois muitas vezes os sintomas passam despercebido, e a pessoa descobre quando ja esta num grau avancado da doenca. Por isso a melhor maneira de descobrir se voce tem diabetes, e fazer um exame de sangue, a glicemia em jejum. Hoje vou deixar aqui os sintomas mais comuns da doenca, se voce tiver mais de 1, procure ja um medico endocrinologista. Se voce precisar urinar com frequencia, especialmente se voce muitas vezes tem que se levantar a noite para ir ao banheiro, pode ser um dos sintomas. Os niveis de acucar no sangue demasiado elevados podem tambem causar a perda de peso rapida, mas esta nao e uma perda de peso saudavel.
Como a circulacao e alterada, a pessoa pode ter a pele afetada como coceiras, ressecamento e ma cicatrizacao. Como os vasos sanguineos sao danificados pelo excesso de glicose circulando, toda a circulacao fica comprometida e entao um pequeno corte ou ferida demora muito mais tempo para cicatrizar. Essa circulacao comprometida tambem pode favorecer o diabetico a sentir formigamento ou amortecimento das maos e pes. IntroductionDiabetes mellitus is an endocrine disorder characterised by inadequate production or use of insulin, resulting in abnormally high blood glucose levels.
IntroductionDiscovery of stem cells by James Till and Ernest McCulloch in 1961, stands as one of the most remarkable medical-research achievements of the 20th century. Stem cells derived from human fetal membranes display multilineage differentiation potential.
Susceptibility of human fetal mesencyhmal stem cells to Kaposi sarcoma-associated herpesvirus. Human herpesvirus-6 encephalitis after unrelated umbilical cord blood transplant in children. JC Virus Leuko-Encephalopathy in Reduced Intensity Conditioning Cord Blood Transplant Recipient with a Review of the Literature. Haematopoietic progenitor cells from adult bone marrow differentiate into cells that express oligodendroglial antigens in the neonatal mouse brain.
Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Ainda assim, se voce tem sintomas, pode ir mais alem e fazer o exame de curva glicemica classico, com coletas a cada 30 minutos num periodo de 2 a 3 horas, e o exame de nivel de insulina.
Os rins precisam trabalhar muito para eliminar toda a glicose que esta no sangue e por isso quem tem glicemia alta urina mais vezes.
Com a glicemia alta, os rins trabalhando a todo o vapor e a necessidade de maior energia (ja que a glicose no sangue nao e utilizada), o organismo passar a utilizar a massa magra. A acantose nigricans, um escurecimento da regiao do pescoso ou bracos tambem e sinal de que  ja ha uma resistancia a insulina. Pacientes com a diabetes muito alterada podem evoluir de um simples corte no pe para uma enorme ferida, que se infeccionar leva ate mesmo a amputacao: e o tal do pe diabetico, que precisa de muito cuidado.
Alem disso, acorda mais vezes e nao dorme bem a noite, pois precisa sempre ir ao banheiro urinar.
Check ups anuais, boa alimentacao, atividade fisica e atencao aos principais sintomas e fundamental para prevenir a diabetes! 6 dicas rapidas para torna-lo mais facilVirginia Sampaio on Preguica de fazer cafe da manha?
Diabetes is a degenerative disease that causes a person to have higher than normal blood sugar as a result of the body not producing enough insulin (Type 1) or sometimes because the cells won’t respond to the insulin being produced (Type 2). High blood glucose leads to the formation of reactive advanced glycation end-products (Feldman et al., 1997), which are responsible for complications such as blindness, kidney failure, cardiovascular disease, stroke, neuropathy and vascular dysfunction.
Visitar um medico oftalmologista frequentemente e fundamental para acompanhar a saude ocular. Estes dois sintomas juntos sao a forma do seu organismo tentar controlar a alta de acucar no sangue. Sabe aquela abobrinha cozidinha, refogada ou aquele brocolis no vapor ou refogadinho de toda semana?
Type 1 diabetes mellitus (insulin-dependent diabetes mellitus) results from the autoimmune destruction of the pancreatic beta cells, whereas type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus) results from insulin resistance and impaired glucose tolerance. Administration of autologous bone marrow derived mononuclear cells in children with cerebral palsy.
Capecchi, and Oliver Smithies were jointly awarded a Nobel Prize in 2007 for their contribution in introducing specific gene modifications in mice by the use of embryonic stem cells. Soleimani, 2011The reversal of hyperglycemia after transplantation of mouse embryonic stem cells induced into early hepatocyte-like cells in streptozotocin-induced diabetic mice, Tissue Cell, (Jan 2011). Typically, the pooled islets isolated from two pancreases are enough to treat a single patient. Gurdon and Shinya Yamanaka were also jointly awarded a Nobel Prize for discovering that mature cells can be reprogrammed to become pluripotent cells. A process called leukapheresis or apheresis is used to obtain PBSCs (Peripheral Blood Stem Cells) for transplantation. Since the enormous potential of stem cells was discovered, it was hoped that they would provide the most effective treatment for diabetes mellitus. For about 2 or 4 days before the apheresis, the patient may be given medication to help increase the number of circulating stem cells in the bloodstream. Over the past two decades, hundreds of studies have looked at the potential of stem cell therapy for treating diabetes mellitus. Successful stem cell therapy would eliminate the cause of the disease and lead to stable, long-term results; hence, the term “pancreatic regeneration” was coined. The machine counts and separates the CD34+ MSC and Progenitor Stem cells that are used in ourA treatment protocol. After careful consideration of the aetiology of diabetes mellitus, scientists have put forward two general treatment strategies: stem cell therapy to treat the autoimmune aspect of the disease, and stem cell therapy to treat the degenerative aspect of the disease.
It was a long-standing belief that cells of the central nervous system once damaged cannot be regenerated. In this review, we focus on stem cell-based therapies aimed at islet regeneration through stem cell or insulin-producing cell (IPC) transplantation.
The medical science of stem cells has finally made restoration of CNS possible which has changed the old concept of medicine. We will also discuss the latest strategies for treating both type 1 and type 2 diabetes mellitus using stem cell therapy, along with the (initially promising) results.
Not too long ago, this therapy was hamstrung by various controversies, ethical and moral issues. But, tremendous progress of research in this field has finally led to its translation from laboratory to innovative cellular therapies.
Cryopreservation is also a cost-effective option for some clients with more severe needs or who may be wanting easy access to matched stem cells for any future treatments.
A variety of cells including embryonic stem cells, adult stem cells, umbilical cord blood cells and induced pluripotent stem cells have been explored as a therapeutic alternative for treating a broad spectrum of neurologic disorders including stroke, Alzheimer’s, Parkinson’s, spinal cord injury, cerebral palsy etc. Some patients with severely degenerative medical conditions will require more transplantation cycles to allow better results.PBSC Collection for Stem Cell TreatmentMSC CD34+ Cell Injections Diabetic patients are usually treated by injecting the stem cells into the pancreatic artery via catheter tube.
Stem cell sources Many different types of stem cells have been used in the research, testing and treatment of diabetes mellitus, including stem cells that can be used to regenerate pancreatic islets, e.g. Patients who cannot safely undergo the catheterization procedure may receive injections via IV drip (intravenously). It is essential to select suitable cells depending on the nature and status of neurological dysfunctions to achieve optimal therapeutic efficacy. Along with the selection of cells, the route of administration also plays an important role to maximize the clinical therapeutic effect of the cell therapy.
Embryonic stem cells Human embryonic stem cells (ESCs) were first isolated at the University of Wisconsin-Madison in 1998 by James Thomson (Thomson et al., 1998). Numerous preclinical studies have been carried out to study the safety of intrathecal, intravenous and direct cerebral implantation. These cells were established as immortal pluripotent cell lines that are still in existence today.
A plethora of published literature is also available to provide evidence of stem cells initiating functional restoration of CNS.
The ESCs were derived from blastocysts donated by couples undergoing treatment for infertility using methodology developed 17 years earlier to obtain mouse ESCs. The postulated mechanisms of action involved are neuromodulation, neuroprotection, axon sprouting, neural circuit reconstruction, neurogenesis, neuroregeneration, neurorepair, and neuroreplacement. We have earned the reputation as a trusted organization that will guide you every step of the way with honest answers,medical opinions and fixed prices only. In view of the fact that stem cell therapy has a promising therapeutic potential in the treatment of neurological disorders, it is important for all the professionals in the medical field to understand the concepts of this upcoming therapeutic strategy.
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However, cells can also be derived from early human embryos at the morula stage (Strelchenko et al. In this chapter, we have focused on stem cell therapy for Cerebral Palsy (CP) which is a heterogeneous group of neurological disorders mainly observed in infants. 2004) after the removal of the zona pellucida using an acidified solution, or by enzymatic digestion by pronase (Verlinsky et al., 2005).
The survival of CP children has increased due to advanced modern medicine which has led to their growing population. We also offer all-Inclusive packages that include short term furnished apartments or Hotel near the treatment center,round trip airport transportation and a personal manager for local or translation assistance.
1).ESCs are pluripotent, which means that they can differentiate into any of the functional cells derived from the three germ layers, including beta cells or insulin-producing cells (IPCs). CP involves impairment of movement, muscle function, and cognitive functioning and the effects range from mild to severe.
The differentiation of ESCs into IPCs is prerequisite for their use as a diabetes mellitus treatment, and may occur either in vivo (after transplantation) or in vitro (before transplantation). In vivo differentiation is based on micro environmental conditions at the graft site, whereas in vitro differentiation requires various external factors that induce the phenotypic changes required to produce IPCs. No biological intervention has been effective for CP and the standard approach is limited to supportive management strategies which do not address the core issue of neural tissue damage.
This means that diabetes mellitus can be treated either by direct transplantation of ESCs, or by indirect transplantation of IPCs that have been differentiated from ESCs. Currently, stem cell based strategies have garnered attention due to their ability of neuroregeneration and neuroprotection in CP.
We have discussed the clinical aspects of stem cell therapy in cerebral palsy supported by various human case studies and clinical trials.
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We have also enumerated our experience and results wherein our subjects were administered autologous bone marrow mononuclear cells. Moreover, using ESCs for pancreatic regeneration carries with it the risk of tumour formation after transplantation.Therefore, the in vitro differentiation of ESCs into IPCs is necessary before they can be used to treat diabetes mellitus. Studies looking at the in vitro differentiation of ESCs into IPCs were first performed in 2001 using mouse cells (Lumelsky et al., 2001). Stem cellsStem cells are defined as “cells that have the ability to renew them continuously and possess pluripotent or multipotent ability to differentiate into many cell types.” [4]These cells exhibit a unique property of “plasticity” where in cells isolated from one tissue convert to cells of different tissues by crossing lineage barriers and adopting the expression profile and phenotype of cells that are unique to other tissues. Researchers then developed a strategy for selecting ESCs expressing genes related to pancreatic cells (e.g. Totipotent cells: These cells have the ability to differentiate into all possible cell types of the human body including extra embryonic and placental cells. Pluripotent cells: These cells have ability to differentiate into any of the three germ layers viz. The differentiation of ESCs into IPCs usually involves differentiation into embryoid bodies.
This relatively long process comprises two phases: the embryoid body stage (4–5 days) and the differentiation stage (30–40 days).
Unipotent cells: These cells have the ability to produce cells only of their own type, but are capable of self-renewal to be classified as a stem cell. ESCs can be isolated from fresh, frozen, dead, excess and genetically deficient embryos, by parthenogenesis and somatic nucleus transfer, from biopsies, and from pluripotent stem cells obtained from adult tissues.In 2001, Assady et al. Although the IPC number and insulin content of these cells was low, this was the first proof-of-principle experiment indicating that human ESCs were a potential source of ?-like cells.
Invitro, they can be indefinitely maintained and expanded as pure populations of undifferentiated cells. They form teratomas which have the potential to degenerate into malignant teratocarcinomas [8] The likelihood of development of tumors in children cannot be overlooked as they have many years of life ahead of them for the tumor formation to occur. Fetal Stem Cells: These cells are isolated either from the aborted fetus or from the extra embryonic structures of the fetal origin such as the amniotic fluid and placenta. Non-haemopoietic mesenchymal stem cells (MSC) are also found in the first trimester fetal blood. They consist of embryonic stem cell-like and other pluripotential stem cells, which can give rise to hematopoietic, epithelial, endothelial, and neural tissues. Pancreatic stem cellsA recent report by Harry Heimberg’s group (Heimberg et al., 2008) describes the existence of pancreatic stem cells in mice. In their most recent study, Heimberg's group ligated the ducts that secrete pancreatic enzymes in adult mice.
The protocols and guidelines for collection and retrieval of cells are still being standardized.

Other disadvantages of use of UCBCs are limited by the fact that minimum necessary dosage of cells for cell engraftment is 1 ? 107 cells per kilogram which includes the total nucleated cell fraction along with stem cells.
Thus, the available dose of autologous cells obtained at birth may be insufficient for transplantation at an older age of the child [13]. Human pancreatic stem cells have also been successfully differentiated into IPCs (Noguchi et al., 2010).
Amount of stem cells found in the cord blood is 10% less than that obtained from the bone marrow.
Islet cells were isolated from the pancreases of human donors using the Ricordi technique modified by the Edmonton protocol.
The isolated cells were then cultured in media specifically designed for mouse or human pancreatic embryonic stem cell culture.
Induced pluripotent stem cells are non-pluripotent adult cells (somatic cells) which have been genetically reprogrammed to form pluripotent cells.
The availability of iPSCs is particularly advantageous for research involving neurological diseases, since it is difficult to obtain diseased tissue sample for study from living patients. They include hematopoietic stem cells, bone marrow derived stem cells, adipose tissue-derived stem cells, neural stem cells amongst others [18] Adult stem cells are found in almost all the tissues of the body and help to maintain and repair organs and tissues throughout a person's life. Mesenchymal stem cellsMSCs are multipotent stem cells that can differentiate into a variety of cell types, such as osteoblasts (bone cells), chondrocytes (cartilage cells) and adipocytes (fat cells) (Anna et al., 2008). These cells are majorly found in the bone marrow, brain, skeletal muscle, liver, pancreas, fat, skin and skeletal muscle. The different types of adult stem cells include multipotent adult progenitor cells, oligodendrocyte progenitor cells neural stem cells, glial progenitor. Maximo, who described a type of cell within the mesenchyme that develops into various types of blood cell. Major sources of adult stem cellsBone marrow: Anterior or posterior superior iliac crest is the preferred site for the bone marrow aspiration.
If bone marrow cannot be obtained from the iliac crest due to positioning difficulties or obesity, sternum may be used in adults. Subsequently, ex vivo clonogenic assays were used to examine the potential of multipotent marrow cells (Friedenstein et al., 1974, 1976). In these assays, stromal cells or MSCs were used as colony-forming unit-fibroblasts (CFU-f). Cells isolated from the bone marrow not only differentiate into blood cells but also into neural tissues. The hematopoietic stem cells (HSCs) are the blood cells which give rise to the myeloid and lymphoid lineages. MSCs have been isolated from many different tissues, including bone marrow (Oyajobi et al..
HSCs also have a potential to transdifferentiate into various nonhematopoietic cell lineages especially neural lineage. It is generally believed that BMMSCs are negative for hematopoietic cell markers such as CD14, CD34, c-kit, SCA1. MSCs can be derived from several adult or infant tissues.MSCs have been successfully differentiated into IPCs in vitro and can reduce blood glucose levels in both animals and humans after transplantation.
The in vitro differentiation of MSCs into IPCs requires certain substances combined with medium stress. They promote angiogenesis, mediate vascular repair, and express several cytoprotective growth factors and cytokines. These cells are also safe and due to its easy availability they are most preferred for cellular therapy. Changes in the glucose concentration within the culture medium are necessary to trigger this process. These cells are used for the treatment of various neurological disorders such as cerebral palsy, stroke, Parkinson’s, Spinal cord injury, etc.
MSCs are commonly cultured in low glucose medium to initiate differentiation before they can be induced to differentiate into IPCs by nicotinamide.
In some studies, epidermal growth factor (EGF) was added to the culture medium during the IPC maturation phase in addition to nicotinamide. They can differentiate into several lineages, including adipose cells, chondrocytes, osteoblasts, neuronal cells, endothelial cells, and cardiomyocytes.
Other sourcesRecent reports suggest that pancreatic duct cells, liver cells, spleen cells, and other cell types have the ability to differentiate into islet cells. Although it is difficult to differentiate adult cells into insulin-producing pancreatic cells, some researchers have shown evidence of pancreatic duct regeneration in mouse models.
When gastrin was injected into mice to induce acinar cells to differentiate into duct cells, these cells became a cellular substrate for the formation of new beta cells, similar to the effects seen in rats receiving glucose injections (Weir and Bonner-Weir et al., 2004). Liver cells originating from the endothelium may also be candidates for this specialised insulin-secreting role (Meivar-Levy et al., 2006).
In experimental cerebral palsy models, infusion of adipose derived stem cells has shown to improve physical activities and cognitive deficits. Another strategy involves the in vivo gene transfer of the pdx-1 gene into liver cells using an adenovirus vector to induce endogenous pdx-1 gene expression.
Similar to pdx-1, betacellulin and neuro-D expression by liver cells yielded sufficient insulin-producing cells in a streptozocin (STZ)-induced diabetic mouse model. These techniques not only induce liver cells to differentiate into beta cells, but also create new islets within the liver itself (Kojima et al., 2003). These cells are readily obtained from routine dental procedures such as removal of impacted third molars, deciduous teeth and have been shown to possess properties similar to neural stem cells and mesenchymal stem cells. Other studies showed that human foetal liver cells transfected with telomerase and pdx-1 can produce insulin and release it into the body. In a recent study, 61 single-cell-derived dermal fibroblast clones were established from human foreskin using a limiting dilution technique. Menstrual Blood stem cells: Recently, stem cells have been identified from the endometrial tissue. These cells were able to differentiate into islet-like clusters when induced using pancreatic-inducing medium and several hormones, including insulin, glucagon and somatostatin, were detectable at both the mRNA and protein levels after induction.
Moreover, transplantation of these islet-like clusters resulted in the release insulin in response to glucose in vitro (Bi et al. Hematopoietic stem cells obtained from PB by leukapheresis have been used for transplantation as an alternative to bone marrow-derived stem cells (BM-stem cells). Various routes of administration of stem cells for cerebral palsyThe appropriate route of cell administration is essential prerequisite for the success of cellular therapy. For the treatment of cerebral palsy, cells are injected via various routes such as intrathecal, intravenous and intracerebral. Intrathecal administration: Intrathecal administration of cells involves delivery of cells via lumbar puncture. This mode of injection allows efficient delivery of cells and the possibility of migration of cells to the tissues other than the damaged ones is avoided. Although diabetes mellitus is caused by destruction of the beta cells within the pancreatic islets, no studies have attempted transplantation directly into the pancreas. In case of cerebral palsy, it is considered to be the safe, feasible and efficacious route of administration.
In cerebral palsy, studies have shown that this route of administration results in positive functional outcomes.
Stem cell transplantationUnlike IPC transplantation, the mechanisms underlying islet regeneration and the reductions in blood glucose levels seen in diabetic patients require further study.
The main questions that need to be answered are: 1) what role do grafted stem cells play in the regeneration of pancreatic islets? Studies have shown that on administering cells intravenously, few cells reach the damaged site while a majority of cells get trapped in the lungs.
2) How will stem cells behave when grafted into the body rather than the pancreas?One type of stem cell that has been used to treat diabetes mellitus and investigated extensively in animal models is MSCs. Pulmonary passage could be one of the major hindrances for intravenous administration of stem cells.
Almost all research on MSC transplantation shows that in vitro or in vivo transplantation of MSCs results in a reduction of blood glucose levels, weight gain and increased longevity.
Hence, for effective result of intravenous stem cell transplantation, it is necessary to increase the number of cells injected.
This leads to migration of cells to the areas of ischemia but the outcome is not as remarkable as compared to the other minimally invasive procedures. In an in vitro model using MSCs derived from human bone marrow and pancreatic islets, Sorvi et al. Additionally, in CP the injury of the brain is diffused and a local injection could be focused on a particular area which might not be as effective. Moreover, MSCs were detected within the pancreatic islets of mice injected with green fluorescent protein (GFP)-positive MSCs (Sorvi et al., 2005).
This result was subsequently confirmed in 2009 by Sordi, who hypothesised that the crosstalk between MSCs and pancreatic islets was driven by the CXCR4-CXCL12 and CX3CR1-CX3CL1 axes (Sordi, 2009).
Mechanism of action of stem cells in cerebral palsyTo understand the mechanism of action of stem cells in the treatment of cerebral palsy, it is important to understand the empirical neuropathophysiology. In spite of the vast and varied etiology; underlying cellular mechanisms, that cause the morbidity or mortality associated with cerebral palsy, are tissue damage caused by hypoxia and ischemia. The clinical manifestations of this cellular damage, depends on a range of factors including the time of insult, the severity of insult and cause of the insult. Using bone marrow-derived MSC transplantation coupled with down-regulation of neurogenin 3 (Ngn3) induced by a recombinant lentivirus encoding two different small hairpin RNAs (shRNAs) for specific interference, they showed the successful engraftment of MSCs. In addition, they found that the endogenous pancreatic stem cells differentiated into IPCs and played a major role in reversing hyperglycaemia (Lin et al., 2009). Recent preclinical, immunohistochemical and imaging evidence suggests periventricular white matter injury (PWMI), particularly damage to oligodendrocytes (OLs) as a primary cause of cerebral palsy [40,41,42]. However, there are cases in which stem cells derived from human umbilical cord blood also move into the pancreas and differentiate into IPCs in immunocompromised diabetic animals without improving hyperglycaemia (Koblas et al., 2009).
PWMI is a spectrum ranging from cystic focal necrotic lesions, periventricular leuckomalacia (PVL) to specific cortical scarring in the deep regions of sulci, Ulegyria to diffuse myelination disturbances. Oligodendrocyte progenitors are abundantly present in the subventricular and periventricualr zones, therefore damage to these cells is seen as PVL in neuroimaging investigations.
The extent of the damage to the white matter and its consequences are dependent on the developmental stage at which the damage occurred, brain vascularization and the type of tissue[43].
Thus, stem cell mobilisation is critical for bone marrow transplantation-induced beta cell regeneration after injury. Figure 2.Phases of Oligodendrocyte developmentVascularization of the brain begins as early as 28th day of gestation with the formation of carotid arteries, followed by the large arteries, their branches, communicating arteries, long penetrating arteries and ends with the formation of short penetrating arteries in the post term period. Damage at pre term leads to focal cystic necrosis in the vascular end zones of the long penetrating arteries causing PVL, damage at term leads to tissue injury at the border zones of the long and short penetrating arteries giving rise to Ulegyria and damage at post term leads to diffuse myelination disturbances caused at the vascular end zones of short penetrating arteries [44]. MSCs prevented beta-cell destruction and development of diabetes mellitus by inducing regulatory T cells (Madec et al., 2009). Subsequently most vulnerable cells, precursors of Oligodendrocytes (OLs), undergo necrosis through apoptosis. Thus, MSC transplantation may prevent islet cell destruction by the immune system seen in type 1 diabetes mellitus and the pancreatic islets can be gradually restored. Oligodendrocytes evolve through an established lineage of OL progenitors to pre OLs to immature OLs to mature OLs.
Other cell types and mechanisms that contribute to pathophysiology of CP are axonal damage and microglial activation [45]. Following this primary insult to the nervous tissue, activation of glial cells leads to secretion of various chemical mediators of tissue necrosis in the neural microenvironment, leading to secondary white matter injury. These mediators are Reactive oxygen and nitrogen species, glutamates, adenosine and inflammatory cytokines like Tumor necrosis factor alpha (TNF-?), interferon gamma (INF-?), Interleukin -1 beta (IL-1?) and superoxide radicals [46]. Hence, stem cell intervention is more successful in these children as the integration of new cells in the brain to carry out the repair process is more effective [47].
Stem cell possess the capacity to home onto the injured sites of brain, as guided by chemo attractant pathway [48].
The effects of cellular therapy are twofold, enhancing the brain tissue repair caused by various paracrine mechanisms and regeneration of neural tissue. Stem cells help in modifying the microglial response by exhibiting immunomodulatory, neurotrophic properties and enhance axonal sprouting. Various neurotrophic factors secreted by the stem cells are connective tissue growth factor, fibroblast growth factor 2 and 7 that are responsible for cell proliferation, interleukins responsible for cytoprotection [49,50,51]. Stem cell therapy restores lost myelin by replacing dead cells with new oligodendrocytes and their progenitors.
Indirectly, it may also support their survival by introducing other cell types able to restore missing enzymes to an otherwise deficient environment [47].
Stem cell therapy also has an anti-inflammatory effect on the neural microenvironment as they reduce the levels of TNF-?,IL-1?, IL-1?, IL-6 and increased levels of IL-10 [52]; therefore, enhancing the endogenous brain repair. Stem cells also secret various growth factors like vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), brain fibroblast growth factor (bFGF). These growth factors initiate neoangiogenesis and induce secretion of hormones like erythropoietin.
The cascade events triggered due to these lead to formation of new vessels as well increased bold flow. Improved blood circulation of the brain thus helps retrieving the lost tissue functions [50].3.
Published literatureSeveral preclinical experiments on animal models of cerebral palsy have been carried out to demonstrate the potential of cell transplantation to minimize damage and promote recovery.
However, limited clinical trials have been initiated to study the effect cell therapy in humans. Human umbilical cord blood cells (hUCBCs) have been explored to a great extent in cerebral palsy.
They protect the mature neurons in the neocortex from injury, bring about near-normalization of brain damage in the subventricular zone (SVZ) leading to significant improvement in behavioral functions.
The long lasting effect of these cells is due to the paracrine effects of hUCBCs which stimulate recovery in the injured brain and protect against further brain damage.
The dimensions of cortical maps and receptive fields, which are significantly altered after injury, are largely restored.

Additionally, the lesion induced hyper-excitability is no longer observed in treated animals compared to control animals. The results demonstrate that hUCB cells reinstall the way central neurons process information by normalizing inhibitory and excitatory processes.
Park et al reported clonal neural stem cells (NSCs) when transplanted into brains of postnatal hypoxic-ischemic (HI) injury mice, home preferentially to and integrate extensively within the ischemic areas. They observed that cells migrated to the lesion site, remained undifferentiated at day 10, and differentiated into oligodendrocyte and neurons at day 42. Although grafted cells finally die there few weeks later, this procedure triggered a reduction in lesion size and an improvement in memory performance compared with untreated animals. But, similar results are difficult to replicate in human cases since the intervention always, cannot be carried out immediately post injury.
Based on this observation, it can also be concluded that earlier the intervention, better is the outcome. They underwent transplantation of neural progenitor cell (NPC) derived from aborted fetal tissue. After 1 year, the developmental level in gross motor, fine motor, and cognition of the treatment group was significantly higher compared to the control group. These results suggested that NPC transplantation is a safe and effective therapeutic method for treating children with severe CP. On follow up, they observed an increase in the GMFM scores and language quotients compared to the control group.
No adverse events were recorded indicating that NSC-like cells are safe and effective for the treatment of motor deficits related to cerebral palsy.
They observed improvement in motor and cognitive dysfunction in children with CP, accompanied by structural and metabolic changes in the brain. They found that this therapy was safe, feasible and led to functional improvements in children which was seen by the change in GMFCS. At 2-months follow-up the boy's motor control improved, spastic paresis was largely reduced, and eyesight was recovered, as did the EEG.
At 40 months, independent eating, walking in gait trainer, crawling, and moving from prone position to free sitting were possible, and there was significantly improved receptive and expressive speech competence (four-word sentences, 200 words). This suggested that autologous cord blood transplantation could be a treatment alternative for cerebral palsy. She was treated with multiple times of intravenous and intrathecal administration of MSCs derived from her young sister and was followed up for 28 months. On follow up, they recorded a significant improvement in motor, sensory, cognitive, and speech. Hence, concluding that intrathecal infusion of autologous BMMNCs is feasible, effective, and safe in CP patients. Six months after the treatment, both cases showed significant functional outcomes which was supported by improvement in PET CT scan.
Ongoing trialsCurrently, there are five clinical trials on stem cell therapy for cerebral palsy registered in clinicaltrials.gov. One of the studies is a combination of phase 1 and phase 2 while the other is a combination of phase 2 and phase 3.
2 studies are from Iran, one evaluating the side effects of bone marrow derived CD133 cells transplantation in cerebral palsy patients and the other studying the safety of multiple intrathecal injections of bone marrow derived CD133 cells.
A study from USA is based on evaluating the safety and effectiveness of a single, autologous, cord blood stem cell infusion for the treatment of cerebral palsy in children. Administration of autologous bone marrow derived mononuclear cells in children with cerebral palsy.Sharma et al, carried out a study on 71 children, wherein they administered 20 cases of cerebral palsy with autologous bone marrow mononuclear cells, intrathecally. Symptoms commonly observed in them were delayed milestones, spasticity, motor impairment, ambulation deficits, cognitive impairment, swallowing and speech problems etc.
Autologous bone marrow MNCs were selected as they are easily obtainable, safe and do not involve any ethical issues. As discussed earlier, intrathecal route of administration is a minimally invasive, safe and an effective procedure as compared to other routes. Studies have also proved that a mixture of cells exhibits more benefits as compared to a single sub fraction of cells. On the day of the transplantation, bone marrow was aspirated under general anesthesia in the operation theatre with aseptic precautions. Approximately, 100 ml of bone marrow (varying between 80 ml and 100 ml, based on the age and body weight) was aspirated from the region of anterior superior iliac spine using the bone marrow aspiration needle and collected in the heparinized tubes. The aspirate was then transferred to the laboratory where the mononuclear cells were separated by the density gradient method.
The separated autologous BMMNCs were immediately injected on the same day, intrathecally using an 18G Touhy needle and epidural catheter at the level between fourth and fifth lumbar vertebrae. Patient was monitored for any adverse events.On mean follow up of 15 months ± 1 month post stem cell administration, improvement was observed in 85% cases. Some minor side effects such as headache, nausea and vomiting were experienced by few children who were self-limiting (resolved within a week) and treated with medications. None of them showed any deterioration on the GMFCS [78]We are also currently conducting a clinical study to assess the efficacy of autologous BMMNC in 64 patients with CP. The unpublished data analysis have shown preliminary results as improvement in oromotor skills, speech, neck holding, sitting, standing and walking balance and significant reduction in muscular tone and dystonic movements. These changes were observed in all types of cerebral palsy over 6 months with varied follow up periods. Oromotor skills (75%), speech (64%), neck holding (100%),Sitting balance (67%), standing balance(67%), walking balance (67%), ambulation (30%), leg movements (54%), overhead movements (38%), distal hand movements (69%), upper limb spasticity (38%), Lower limb spasticity (38%), trunk muscle tone (36%), trunk dissociation (30%)Percentage improvement noted in patients of quadriplegic cerebral palsy was as follows. Oromotor skills (58%), speech (40%), neck holding (94%),Sitting balance (48%), standing balance(27%), walking balance (21%), ambulation (13%), involuntary movements (25%), upper limb spasticity (51%), Lower limb spasticity (50%), trunk muscle tone (36%) Percentage improvement noted in patients with other types of cerebral palsy was as follows. Objective imaging evidenceVarious clinical outcome measures have been devised to measure changes in sensory, motor, cognitive, perceptual and Behaviour functions in CP. MRI scans not only help reveal the underlying pathology of CP, but it also correlates with the clinical findings. Principle mechanisms underlying the benefits of cellular therapy are the changes brought about in the microenvironment of cells reducing cell necrosis, ischemia and hypoxia.
These changes therefore cannot be measured on a plane MRI and hence it is not a sensitive tool to monitor the effects of stem cell therapy. Functional neuroimaging on the other hand may be an appropriate option to monitor the finer changes at cellular level. The basic principle underlying the functional neuroimaging of the brain is that the cerebral blood flow and metabolism is associated with neuronal activity.
Measurement of the tissue function is therefore a preferred outcome measure to monitor the effects of cellular therapy. Positron Emission Tomography – Computed Tomography (PET – CT) is one of the techniques of functional neuroimaging that measures the metabolism of the nervous tissue in terms of Fleuro-deoxy glucose (FDG) uptake. FDG is a radioactive glucose analogue that undergoes glycolysis in the same manner as that of glucose.
Once it has been metabolized to FDG – 6 – Phosphate it cannot be further metabolized and is trapped inside the cell due to the impermeability of the cell membrane for this molecule. Photons emitted by this radioactive isotope are then measured to identify concentration of FDG in the nervous tissue [84]. This is expressed as a ratio of the actual uptake and the calculated presumed uptake of FDG, standard uptake value [85].
Because of its ability to measure the finer changes in tissue metabolism, FDG PET-CT holds a great potential as a monitoring tool. Various guidelines are available for appropriate standardization, image acquisition and interpretation during PET-CT scanning. The tissue metabolism of 18F-FDG is the same in adult and children and the dose administered in children is “as low as reasonably achievable”. Various adjustments with regards to scanning technology and measurement period are made to enhance the quality of the image with the administered dose [89]. PET-CT is sensitive to measure the cellular changes and it is a standardized imaging modality which makes it a good monitoring tool to assess the effects of cellular therapy.
In our previous case studies involving cerebral palsy patients treated with autologous bone marrow derived mononuclear cells (BMMNCs), the clinical outcome was correlated with changes in the PET scan. In one case of a 20 year old CP patient with co morbid intellectual disability, a repeat PET-CT scan showed significant increase in the FDG uptake in various affected areas of the brain, which correlated with the clinical improvement in social behavior, balance and motor control.
However the MRI remained unchanged (76).In another case of a 2 year old child with cerebral palsy, we observed similar correlation of clinical improvement with the PET-CT changes in metabolism. These clinical changes were synonymous with the increased FDG uptake in the bilateral mesial temporal structures, right basal ganglia, frontal, parietal, temporal and occipital lobes. Functional MRI is also one of the emerging techniques to study the functional outcome of the intervention. The technique of fMRI is based on Blood oxygenation level dependent (BOLD) contrast between rest and activated states of human brain. Hence, fMRI may be effectively used to monitor the therapeutic outcome of stem cell therapy and should be studied further. Role of rehabilitation in combination with stem cell therapyFor a long time, rehabilitation has been the standard approach for cerebral palsy. The goal of rehabilitation in cerebral palsy is to develop coordination, build strength, improve balance, maintain flexibility, optimize physical functions, manage spasticity and maximize independence. Various therapeutic regimens aim to enhance particular clinical, functional and psychosocial consequences of CP. Physiotherapy, makes use physical modalities to muscle spasticity, increase flexibility, balance and co-ordination, build strength and enhance function. Multiple medical and surgical regimens are also instituted to deal with these physical impairments. Botox injections are most commonly used to reduce spasticity of the muscles, but the effects are short lived. A variety of surgical techniques are utilized to correct deformities.Occupational therapy is focused at therapeutic regimens to improve cognitive abilities of the child and increase participation in activities of daily and social living. Children with CP most often present with poor oromotor control and speech disorders, speech therapy aims at correcting these impairments. It helps to improve the quality of life by addressing co-morbid psychological disturbances and cognitive impairments.
All of the rehabilitative modalities face the fundamental limitation of inability to repair the damage to the nervous tissue. Wright and Nicholson and Sommerfeld et al have demonstrated that physical therapy alone does not show a consistent benefit in cerebral palsy. It also increases angiogenesis and oxygen supply to the brain thereby improving the cognitive function.
Regular exercise induces suppression of pro-inflammatory cytokines and up regulation of anti-inflammatory cytokines in various tissues of the body including brain. In addition, mobilization of stem cells, enhanced homing, improved angiogenesis exercise also exerts immunomodulatory effects.
Exercise and rehabilitation has a synergistic effect for the benefits of cell transplantation.
Although cellular therapy for cerebral palsy has moved from the preclinical studies to bedside therapy; evidence remains inconclusive regarding multitude of variables.
These variables are pertaining to cerebral palsy and cellular therapy.Cerebral palsy is a heterogeneous group of disorders. Pre-clinical models of effects of cellular therapy in cerebral palsy are far from the ideal state and show benefits only in acute injury. Majority of the human application of stem cells in cerebral palsy is for individuals who already have established pathology, hence at a chronic stage.
Animal models of chronic injury are therefore required to study the efficacy and mechanism of action of stem cells. The individuals suffering from cerebral palsy are from various age groups, and present with varied kinds and severities of clinical manifestations; there is only a limited evidence about which of these groups will benefit the most from cellular therapy. Only preliminary evidence using basic research methodologies is available for the effects of cellular therapy in humans.
We require more double blind, randomized, multicenter controlled clinical trials to prove the safety and feasibility of stem cells. The evidence available is heterogeneous in methodology, patient population, outcome measures and cellular therapy provided.
Stem cells provide their beneficial effects through numerous mechanisms; it is difficult to underpin the exact mechanism of action of stem cells. Types, sources and numbers of cells administered, frequency of transplantation, time of transplantation are concerns which require attention imperatively.
It is important to not only conduct more trials but also to standardize research protocols to allow comparison. Comparative studies will help in establishing the most effective cell based therapy for cerebral palsy.Apart from these issues, development and validation of outcome measures to obtain evidence of the efficacy of intervention is very important.
Modalities should be developed to study the effect of cell transplantation at a cellular level.
Outcomes that can successfully assess these cellular changes are measuring the serum, plasma and cerebrospinal fluid biomarkers, which are invasive.
PET-CT scan has been used as an outcome to assess the effects of cellular therapy however it is required to further explore its various components in depth. It is therefore necessary to explore how functional imaging can provide us a better understanding of the cellular mechanisms. ConclusionStem cell therapy has been extensively studied but still needs to be standardized before it becomes a definitive treatment modality.
Autologous BMMNCs are safe and feasible option but their effectiveness needs more clinical trials.

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