Cellular repair is a promising strategy for treating central nervous system (CNS) disorders. Several strategies have been contemplated including replacement of neurons or glia that have been lost due to injury or disease, use of cellular grafts to modify or augment the functions of remaining neurons and/or use of cellular grafts to protect neural tissue by local delivery of growth or trophic factors. Depending on the specific disease target, there may be one or many cell types that could be considered for therapy. In each case, an additional variable must be considered--the role of the immune system in both the injury process itself and in the response to incoming cells. Cellular transplants can be roughly categorized into autografts, allografts and xenografts. Despite the immunological privilege of the CNS, allografts and xenografts can elicit activation of the innate and adaptive immune system. In this article, we evaluate the various effects that immune cells and signals may have on the survival, proliferation, differentiation and migration/integration of transplanted cells in therapeutic approaches to CNS injury and disease.
"This response of hESC DA neurons to guidance cues provides an additional criterion to monitor the differentiation of hESC DA neurons in vitro and to determine if they are mimicking their native counterparts in vivo, and may thus act as appropriate replacements for diseased DA neurons in PD patients. hESC DA neurons can still respond to guidance cues in the presence of cytokines Inflammatory cytokines have pleiotropic effects in the central nervous system, but their potential effects on neuron health or function after transplantation therapy is not well understood (Chen and Palmer, 2008). Inflammatory cytokines can inhibit spinal cord regeneration (Nakamura et al., 2003), and TNFα is implicated in the progression of PD (Sriram et al., 2002). "
[Show abstract][Hide abstract] ABSTRACT: Dopaminergic neurons derived from human embryonic stem cells will be useful in future transplantation studies of Parkinson's disease patients. As newly generated neurons must integrate and reconnect with host cells, the ability of hESC-derived neurons to respond to axon guidance cues will be critical. Both Netrin-1 and Slit-2 guide rodent embryonic dopaminergic (DA) neurons in vitro and in vivo, but very little is known about the response of hESC-derived DA neurons to any axonal guidance cues. Here we examined the ability of Netrin-1 and Slit-2 to affect human ESC DA axons in vitro. hESC DA neurons mature over time in culture with the developmental profile of DA neurons in vivo, including expression of the DA neuron markers FoxA2, En-1 and Nurr-1, and receptors for both Netrin and Slit. hESC DA neurons respond to exogenous Netrin-1 and Slit-2, showing an increased responsiveness to Netrin-1 as the neurons mature in culture. These responses were maintained in the presence of pro-inflammatory cytokines that might be encountered in the diseased brain. These studies are the first to evaluate and confirm that suitably matured human ES-derived DA neurons can respond appropriately to axon guidance cues.
"We could also show in the present study that L1 overexpressing SENAs, in comparison to the wild-type SENAs, decreased the number of microglial cells in the host tissue. The reason why the number of microglial cells was decreased in the vicinity of L1 overexpressing versus wild-type grafts is currently not understood but encourages further investigation of the role of L1 on immune system cells in the brain as the immune response of the brain to injury and grafted tissue is an important issue in neurodegenerative diseases and in stem cell biology (Barker and Widner, 2004; Chen and Palmer, 2008; Ideguchi et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Parkinson's disease is the second most common neurodegenerative disease, after Alzheimer's disease, and the most common movement disorder. Drug treatment and deep brain stimulation can ameliorate symptoms, but the progressive degeneration of dopaminergic neurons in the substantia nigra eventually leads to severe motor dysfunction. The transplantation of stem cells has emerged as a promising approach to replace lost neurons in order to restore dopamine levels in the striatum and reactivate functional circuits. We have generated substrate-adherent embryonic stem cell-derived neural aggregates overexpressing the neural cell adhesion molecule L1, because it has shown beneficial functions after central nervous system injury. L1 enhances neurite outgrowth and neuronal migration, differentiation and survival as well as myelination. In a previous study, L1 was shown to enhance functional recovery in a mouse model of Huntington's disease. In another study, a new differentiation protocol for murine embryonic stem cells was established allowing the transplantation of stem cell-derived neural aggregates consisting of differentiated neurons and radial glial cells into the lesioned brain. In the present study, this embryonic stem cell line was engineered to overexpress L1 constitutively at all stages of differentiation and used to generate stem cell-derived neural aggregates. These were monitored in their effects on stem cell survival and differentiation, rescue of endogenous dopaminergic neurons and ability to influence functional recovery after transplantation in an animal model of Parkinson's disease. Female C57BL/6J mice (2 months old) were treated with the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intraperitoneally to deplete dopaminergic neurons selectively, followed by unilateral transplantation of stem cell-derived neural aggregates into the striatum. Mice grafted with L1 overexpressing stem cell-derived neural aggregates showed better functional recovery when compared to mice transplanted with wild-type stem cell-derived neural aggregates and vehicle-injected mice. Morphological analysis revealed increased numbers and migration of surviving transplanted cells, as well as increased numbers of dopaminergic neurons, leading to enhanced levels of dopamine in the striatum ipsilateral to the grafted side in L1 overexpressing stem cell-derived neural aggregates, when compared to wild-type stem cell-derived neural aggregates. The striatal levels of gamma-aminobutyric acid were not affected by L1 overexpressing stem cell-derived neural aggregates. Furthermore, L1 overexpressing, but not wild-type stem cell-derived neural aggregates, enhanced survival of endogenous host dopaminergic neurons after transplantation adjacent to the substantia nigra pars compacta. Thus, L1 overexpressing stem cell-derived neural aggregates enhance survival and migration of transplanted cells, differentiation into dopaminergic neurons, survival of endogenous dopaminergic neurons, and functional recovery after syngeneic transplantation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.
"Despite differences in adaptive immune signaling between the periphery and the CNS, the CNS is still fully capable of rejecting xenografts and allografts (reviewed in (Chen and Palmer, 2008). For example, in one study, xenograft transplants of embryonic brain tissue into the brains of mice were rejected, but allografts survived at least 42 days (Mirza et al., 2004). "
[Show abstract][Hide abstract] ABSTRACT: Neural stem cells (NSCs) lie at the heart of central nervous system development and repair, and deficiency or dysregulation of NSCs or their progeny can have significant consequences at any stage of life. Immune signaling is emerging as one of the influential variables that define resident NSC behavior. Perturbations in local immune signaling accompany virtually every injury or disease state, and signaling cascades that mediate immune activation, resolution, or chronic persistence influence resident stem and progenitor cells. Some aspects of immune signaling are beneficial, promoting intrinsic plasticity and cell replacement, while others appear to inhibit the very type of regenerative response that might restore or replace neural networks lost in injury or disease. Here we review known and speculative roles that immune signaling plays in the postnatal and adult brain, focusing on how environments encountered in disease or injury may influence the activity and fate of endogenous or transplanted NSCs.
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