Transplantation Of Fetal Brain Tissue Research Articles

Importance of stoichiometry in cells science: iPSC, CNS leukocytes, and more

the hope of becoming the source and basis of sideeffect–free ‘‘medication’’ and repair of deficits in our body,stem cells have been, for a few decades, of interest in basic cellresearch, regenerative medicine, and public opinion. Cytome-try was from the beginning a guiding technology in thisendeavor. The substantial past and present scientific interest isreflected by the fact that publications on stem cells and theirunequivocal identification are the ‘‘best sellers’’ regarding cita-tion and download rates also in the cytometry-focused litera-ture (1). Nevertheless, stem cell therapy still plays a minor rolein clinical practice. The main stem cell therapy is allogenic orautologous bone marrow transplantation in cancer or insevere life-threatening autoimmune diseases such as rheuma-toid arthritis. This transplantation is either done by crudebone marrow allografting or by using purified (i.e., sorted orotherwise enriched) material.Another far less frequent application is transplantation offetal brain tissue in Parkinson’s disease, rendering (temporary)relief from the symptoms. Fetal brain transplant in Hunting-ton’s disease was far less successful as indicated by clinicaltrials enrolling a limited number of patients. In addition,transplantation of parts of the fetal brain is a continuing issueof ethical concern. One of the reasons for the limited applica-tion of stem cell therapy in regenerative medicine is the limita-tion of appropriate cell sources. Mesenchymal stem cells fromfatty tissue (2), as one example, can be relatively easily har-vested but may be limited in their regenerative abilities.Consequently, the discovery of embryonic pluripotentstem cells has led to both a great deal of activity and hype inresearch for novel cell-based therapies. As ethical issuesinvolved in using embryonic stem cells exist, only a limitednumber of countries equipped with appropriate high-endresearch knowledge and technology can embrace these cells fortherapy development.Therefore, the discovery of inducible pluripotent stemcells (iPSCs)—somatic cells (of in principle any type) that canbe reprogrammed by the transfection of a limited number oftranscription factors to become pluripotent—was an impor-tant breakthrough. By their creative and diligent work, thegroup of Shinya Yamanaka from Kyoto University in Japandiscovered that the transfection of only four genes was suffi-cient to reprogram somatic cells to become iPSCs and formany possible cell type of an organism (3).How to optimize the process of transfection to producemaximum numbers of reprogrammed cells and how to per-form appropriate quality control of yield and cell type remainsa central issue. Tiemann and coworkers from Hannover andM€unster in Germany (this issue, page 426) developed a poly-chromatic flow cytometry approach by attaching each of thefour transfected transcription factors (Oct4, c-Myc, Sox2, andKlf4) to four different fluorescent proteins. Quadruplet posi-tive cells contain the reprogrammed iPSCs that can then besorted and cloned. By testing different stoichiometric combi-nations of these transcription factor expression levels,the authors were able to optimize iPSC yield and quantitateoptimal transcription factor levels.The importance of polychromatic cytometry has beenapplied to identify unusual biological material in the pri-mate brain. Bischoff from the University of G€ottingen,Germany and colleagues (this issue, page 436) focusedtheir interest on cells of the immune system infiltratingthe brain. The quantity and composition of these cells canrender information on inflammation processes in neuro-logical diseases and also in stem cell transplantation,

Function Recovery after Transplantation of Fetal Brain Tissue into Injured Spinal Cord in Experimental Rats

Rakei, S.M., Rahmanian, A., Saffarian, A., Shafeian, R. and Mehrabani, D. 2009. Function recovery after transplantation of fetal brain tissue into injured spinal cord in experimental rats. J. Appl. Anim. Res., 36: 303–306. To determine the effect of transplantation of fetal brain tissue on regeneration of injured spinal cord and the limb function recovery, forty 30-week old male Sprague-Dawley 350–450 g rats were randomly and equally divided into two groups. In 5 pregnant rats the fetuses were removed and the embryonic brain tissues were sectioned into 0.05 mm segments under microscope. The vertebral column was exposed and a 0.1 mm segment of spinal cord medulla at the T10-T11 level was completely dissected in all rats of both groups. A 0.05 mm segment of rat fetus brain was implanted into the injured section of spinal cord of all rats in the case group. No further intervention was done in the control group. After 24 h lower extremity paraplegia was confirmed in all rats. After six weeks, no locomotor improvement was seen in the control group (Basso-Beattie-Bresnahan locomotor rating scale, BBB=0). 15% of rats in the case group had some degrees of recovery from spinal cord injury. Our findings suggest that fetal neural transplants could potentially be an effective surgical intervention for treatment of SCI even though more investigations are warranted.

Stem cell transplantation

Stem cell transplantation

Transplantation of fetal brain tissue into the site of intracerebral hemorrhage in rats

The purpose of this study was to evaluate whether transplantation of fetal forebrain tissue into the hematoma site of rats with intrastriatal hemorrhage could improve the final neurological outcome. Nine to twelve days after collagenase-induced intracerebral hemorrhage, day 14 fetal forebrain fragments were transplanted into hematoma site. Quantitative measures of behavioral function were repeatedly evaluated until the rats were killed 10 weeks after grafting. Histology was used to assess the survival of the grafts and overall brain morphology. Surviving grafts were located in the residual cavity at the hematoma site. However, comparison of rats with live transplants to control rats with no transplant, sham transplant, or dead tissue transplant revealed no statistically significant differences in any of the motor tests.

The LHRH pulse generator: A mediobasal hypothalamic location

The location and mechanism of LHRH pulse generator are discussed based on our series of experiments. Suckling stimulus is a novel stimulus that inhibits LH pulses without any cooperation from ovarian steroids, unlike other stimuli such as stress, photoperiod etc. It is directly involved in suppressing the activity of the LHRH pulse generator. The information from teats suckled by pups or babies is conveyed dorsally to the mediobasal hypothalamus (MBH), where the LHRH pulse generator may be located. Experiments using various types of deafferentation and fetal brain tissue transplantation confirmed that the LHRH pulse generator is located in the MBH and suggested that LHRH pulse generator consists of nonLHRH neurons. Endogenous excitatory amino acid is one of the possible neurotransmitters that regulate LHRH release at the nerve terminal in ME.

Regulating Transfer and Use of Fetal Tissue in Transplantation Procedures: The Ethical Dimensions

For twenty years scientists have worked to find an effective treatment to ease the quivering, the stiffness, and the difficulty in controlling bodily movements which are the primary symptoms of Parkinson's disease. The disease can be treated with L-dopa, a drug that mimics the dopamine that coordinates neural transmission in the human brain, which Parkinson's sufferers have ceased to produce in sufficient quantities. The L-dopa, however, produces damaging side-effects and sometimes proves ineffectual. Researchers discovered in animal experiments that the effects of a laboratory-developed disease simulating Parkinson's disease could be mitigated using fetal brain tissue transplants, which produced the natural dopamine the animals’ cells failed to produce adequately.These experiments were replicated with human subjects, and fetal tissue transplants have shown great potential as a treatment for Parkinson's disease. Fetal tissue is ideal for transplantation because it is in a stage of primitive development in which it adjusts easily to a new environment.

Neural grafts attenuate behavioral deficits produced by early radiation-induced hypoplasia of fascia dentata granule cells

Localized X-irradiation of the mitotic cells in the neonatal rat hippocampus produces a discrete hypoplasia of the fascia dentata granule cell layer. This brain damage inhibits the acquisition of a passive avoidance task, and stimulates spontaneous perseverative turning (without reversals) in a plastic hemisphere apparatus. Here we report how transplantation of fetal brain tissue can attenuate these radiation-induced behavioral deficits. The partially shielded cerebral hemispheres of neonatal rats received fractionated exposures to 13 Gray (Gy) of X-rays during the first 16 days post partum. This procedure depleted 90% of the hippocampal granule cells while sparing other brain areas. Control animals were sham irradiated. Baseline behavioral tests were conducted when subjects reached an average age of 147 ± 4 days. We recorded behavioral parameters known to be sensitive to hippocampal damage: (1) passive avoidance performance, and (2) perseverative spontaneous turning without reversals. Irradiated subjects later (average age= 182 ± 4days) received intracerebral transplants of either fetal (E20–21) neurons/neuronal precursors from the fascia dentata or cerebral cortex (control grafts). Additional controls (both irradiated and sham-irradiated) experienced sham surgical procedures or received no surgical manipulation. Two post-surgical behavioral retests were accomplished when rats were 265 ± 5 and 351 ± 6 days old. Rats were then sacrificed and brains were treated histologically to assess radiation-induced brain damage, graft survivability and graft locus. Both hippocampaa and cerebral cortex grafts generally facilitated performance on the passive avoidance task. This effect was most prominent during the first post-surgical test. Hippocampal transplants (especially those found to reside in the damaged hippocampus) also significantly attenuated perseverative spontaneous rotation at the time of the final post-surgical test series. Cortex grafts found within the damaged hippocampus did not ameliorate perseverative movements, while cortex grafts located outside the hippocampus significantly reduced this behavioral deficiency. These data suggest that selected behavioral deficits may be attenuated by transplanting fetal neural tissue long after early radiation-induced brain damage. The success of these procedures depends on a number of factors including: (1) the behaviors chosen for analysis, (2) the time after transplantation that behavioral tests are conducted, and (3) the source and final location of the donor neural tissue.

Functional effects of fetal striatal transplants

Much interest has been generated in recent years by the finding that fetal brain tissue transplants into adult brain can survive and grow in the host brain. Most work has been done transplanting relatively homogeneous populations of dopaminergic nigral neurons. However, it is now clear that the more complex fetal striatal tissue, which contains multiple neuronal types, will also survive and grow when transplanted into excitotoxin-lesioned adult striatum. We review herein studies demonstrating that the fetal striatal transplants are functional in that they can elicit changes in behavior in the transplant recipients. The striatal transplants reverse the locomotor hyperactivity characteristic of bilateral excitotoxin lesions. However, there is some controversy about the reversal of the abnormal apomorphine- and amphetamine-induced locomotor responses by fetal striatal transplants into excitotoxin-lesioned striatum and the presence or absence of dopamine receptors within the transplanted tissue. We review the evidence for and against the existence of neuroanatomical connections between the host brain and the transplanted fetal striatal tissue. We also point out the possibility of neurotrophic factors mediating the recovery of spontaneous locomotor activity in light of recent evidence that neurotrophic factors may mediate the functional recovery following transplants of adrenal medulla tissue into dopaminergic deafferented striatum.

Transplantation of fetal brain tissue

Fetal brain tissue transplanted to the brain of an adult mammalian host is known to develop within this environment. The grafted tissue also forms connections with the host brain and can produce recovery from behavioral deficits associated with destruction of parts of the host brain. The ability of grafts of fetal brain tissue to both develop in and form electrophysiologically viable connections with brains previously exposed to neurotoxins is discussed in this review. Restoration of neurotoxin-induced behavioral dysfunction by fetal brain grafts is also discussed. Finally, several uses for neural transplantation in neurotoxicological research are suggested. These uses include restoration of behavioral function, identification of the particular structures responsible for observed behavioral deficits, from among several structures damaged by an environmental neurotoxin, and identification of mechanisms underlying neurotoxicity.

Chapter 4 Fetal brain tissue transplants and recovery of locomotion following damage to sensorimotor cortex in rats

Publisher Summary Fetal brain tissue transplants have been shown to be effective in reducing motor impairments accompanying nigrostriatal damage. This chapter examines whether fetal brain transplants would be effective in reducing the motor impairment that occurs following sensorimotor cortex ablations. The chapter discusses experiments with following objective: (1) can fetal brain transplants facilitate recovery of locomotion following damage to sensorimotor cortex, and (2) will the combination of fetal brain transplants and G MI ganglioside treatments enhance recovery of locomotion following sensorimotor cortex damage. Based on the experimental results, it appears that fetal brain tissue transplants from different sites or of different fetal ages fail to produce a demonstrable enhancement of recovery after bilateral damage to sensorimotor cortex. The specific location and type of cerebral injury may be a factor to consider in deciding upon, whether to employ transplants to promote recovery from traumatic injury. The effects of the combined treatment of G MI gangliosides and fetal brain transplants are different from either of these treatments alone. These findings indicate that limited functional recovery can be enhanced by combining transplants with systemic injections of putative neurotrophic factors.

Fetal brain tissue transplants reduce visual deficits in adult rats with bilateral lesions of the occipital cortex

Fetal brain tissue from the occipital or the frontal cortex was implanted into the damaged occipital cortex of adult rats. The animals receiving grafts of embryonic frontal cortex showed partial restoration of brightness discrimination while recipients given homologous implants of occipital cortex were as impaired as those animals with lesions alone. Neither frontal nor occipital grafts aided in the performance of a pattern discrimination problem; both groups of brain-damaged animals were unable to learn the task. Nonetheless, both groups of animals had viable and enlarged grafts with similar neuronal and glial profiles.