Stem cells have been widely assumed to be capable of replacing lost or damaged cells in a number of diseases, including Parkinson's disease (PD), in which neurons of the substantia nigra (SN) die and fail to provide the neurotransmitter, dopamine (DA), to the striatum. We report that undifferentiated human neural stem cells (hNSCs) implanted into 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated Parkinsonian primates survived, migrated, and had a functional impact as assessed quantitatively by behavioral improvement in this DA-deficit model, in which Parkinsonian signs directly correlate to reduced DA levels. A small number of hNSC progeny differentiated into tyrosine hydroxylase (TH) and/or dopamine transporter (DAT) immunopositive cells, suggesting that the microenvironment within and around the lesioned adult host SN still permits development of a DA phenotype by responsive progenitor cells. A much larger number of hNSC-derived cells that did not express neuronal or DA markers was found arrayed along the persisting nigrostriatal path, juxtaposed with host cells. These hNSCs, which express DA-protective factors, were therefore well positioned to influence host TH؉ cells and mediate other homeostatic adjustments, as reflected in a return to baseline endogenous neuronal number-to-size ratios, preservation of extant host nigrostriatal circuitry, and a normalizing effect on ␣-synuclein aggregation. We propose that multiple modes of reciprocal interaction between exogenous hNSCs and the pathological host milieu underlie the functional improvement observed in this model of PD.1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine ͉ dopamine ͉ Parkinson's disease ͉ synuclein ͉ tyrosine hydroxylase D egeneration of dopamine (DA) neurons in the substantia nigra (SN) and the consequent deficit of DA release in the striatum and other target areas appear to be responsible for the characteristic manifestations of Parkinson's disease (PD). Although substantial improvements result from the systemic administration of the DA precursor L-DOPA or DA agonists, such pharmacological replacement does not address the etiology of the disease, provide a permanent redress of the pathophysiology, or forestall progression of the degenerative process. It does, however, support the idea that DA provided by exogenous replacement cells might be therapeutic, a notion verified in rodents (1-3) and monkeys (4 -6), where grafts of fetal DA neurons led to improvements in biochemical and behavioral indices of DA deficiency. However, in graft studies, the improvements in Parkinsonism have been limited and variable (see review in ref. 7). Therefore, we hypothesized that, in addition to DA replenishment, PD treatment should also restore functional equilibrium in the host SN-striatal system. A clinically relevant strategy might be to implant human neural stem cells (hNSCs) and progenitor cells constitutively capable of multiple actions, including neural differentiation and cytokine secretion, and allow them to develop within the PDaffected brains of nonhuman ...

Human embryonic stem cells (hESCs) are genetically stable with unlimited expansion ability and unrestricted plasticity, proffering a pluripotent reservoir for in vitro derivation of a large supply of disease-targeted human somatic cells that are restricted to the lineage in need of repair. There is a large healthcare need to develop hESC-based therapeutic solutions to provide optimal regeneration and reconstruction treatment options for the damaged or lost tissue or organ that have been lacking. In spite of controversy surrounding the ownership of hESCs, the number of patent applications related to hESCs is growing rapidly. This review gives an overview of different patent applications on technologies of derivation, maintenance, differentiation, and manipulation of hESCs for therapies. Many of the published patent applications have been based on previously established methods in the animal systems and multi-lineage inclination of pluripotent cells through spontaneous germ-layer differentiation. Innovative human stem cell technologies that are safe and effective for human tissue and organ regeneration in the clinical setting remain to be developed. Our overall view on the current patent situation of hESC technologies suggests a trend towards hESC patent filings on novel therapeutic strategies of direct control and modulation of hESC pluripotent fate, particularly in a 3-dimensional context, when deriving clinically-relevant lineages for regenerative therapies.

Human embryonic stem cells (hESCs) are genetically stable with unlimited expansion ability and unrestricted plasticity, proffering a pluripotent reservoir for in vitro derivation of a large supply of disease-targeted human somatic cells that are restricted to the lineage in need of repair. There is a large healthcare need to develop hESC-based therapeutic solutions to provide optimal regeneration and reconstruction treatment options for the damaged or lost tissue or organ that have been lacking. In spite of controversy surrounding the ownership of hESCs, the number of patent applications related to hESCs is growing rapidly. This review gives an overview of different patent applications on technologies of derivation, maintenance, differentiation, and manipulation of hESCs for therapies. Many of the published patent applications have been based on previously established methods in the animal systems and multi-lineage inclination of pluripotent cells through spontaneous germ-layer differentiation. Innovative human stem cell technologies that are safe and effective for human tissue and organ regeneration in the clinical setting remain to be developed. Our overall view on the current patent situation of hESC technologies suggests a trend towards hESC patent filings on novel therapeutic strategies of direct control and modulation of hESC pluripotent fate, particularly in a 3-dimensional context, when deriving clinically-relevant lineages for regenerative therapies.

Multipotent human neural stem cells (hNSC) have traditionally been isolated directly from the central nervous system (CNS). To date, as a therapeutic tool in the treatment of neurologic disorders, the most promising results have been obtained using hNSC isolated directly from the human fetal neuroectoderm. The propagation ability of such tissue-derived hNSC is often limited, however, making it difficult to establish a large-scale culture. Following engraftment, these hNSC often show low efficiency in generating the desired neuronal cells necessary for reconstruction of the damaged host milieu and, as a result, have failed to give satisfactory results in clinical trials so far. Alternatively, human embryonic stem cells (hESC) offer a pluripotent reservoir for in vitro derivation of a rich spectrum of well-characterized neural-lineage committed stem/progenitor/precursor cells that can, theoretically, be picked at precisely their safest and most efficacious state of plasticity to meet a given clinical challenge. However, the need for ‘foreign’ biologic additives and multilineage differentiation inclination may make direct use of such cell-derived hNSC in patients problematic. The hNSC, when derived from pluripotent cells under protocols presently employed in the field, tend to display not only a low efficiency in neuronal differentiation, but also an inclination for phenotypic heterogeneity and instability and, hence, increased risk of tumorigenesis following engraftment. For hNSC derived in vitro to be used safely in therapeutic paradigms, it requires conversion of human pluripotent cells uniformly to cells that are restricted to the neural lineage in need of repair. Developing strategies for direct induction of human pluripotent cells exclusively into neural-committed progenies at a broad range of developmental stages will allow a large supply of optimal therapeutic hNSC tailor-made for safe and effective treatment of particular neurologic diseases and injuries in patients.