Isabel Liste

Progress in Stem Cell Therapy for Major Human Neurological Disorders

Human neurological disorders such as Alzheimer’s disease (AD), Parkinson’s disease, stroke or spinal cord injury are caused by the loss of neurons and glial cells in the brain or spinal cord in the Central Nervous System (CNS). Stem cell technology has become an attractive option to investigate and treat these diseases. Several types of neurons and glial cells have successfully been generated from stem cells, which in some cases, have ameliorated some dysfunctions both in animal models of neurological disorders and in patients at clinical level. Stem cell-based therapies can be beneficial by acting through several mechanisms such as cell replacement, modulation of inflammation and trophic actions. Here we review recent and current remarkable clinical studies involving stem cell-based therapy for AD and stroke and provide an overview of the different types of stem cells available nowadays, their main properties and how they are developing as a possible therapy for neurological disorders.

Current advances in the generation of human iPS cells: implications in cell-based regenerative medicine

Over the last few years, the generation of induced pluripotent stem cells (iPSCs) from human somatic cells has proved to be one of the most potentially useful discoveries in regenerative medicine. iPSCs are becoming an invaluable tool to study the pathology of different diseases and for drug screening. However, several limitations still affect the possibility of applying iPS cell‐based technology in therapeutic prospects. Most strategies for iPSCs generation are based on gene delivery via retroviral or lentiviral vectors, which integrate into the hosts cell genome, causing a remarkable risk of insertional mutagenesis and oncogenic transformation. To avoid such risks, significant advances have been made with non‐integrative reprogramming strategies. On the other hand, although many different kinds of somatic cells have been employed to generate iPSCs, there is still no consensus about the ideal type of cell to be reprogrammed. In this review we present the recent advances in the generation of human iPSCs, discussing their advantages and limitations in terms of safety and efficiency. We also present a selection of somatic cell sources, considering their capability to be reprogrammed and tissue accessibility. From a translational medicine perspective, these two topics will provide evidence to elucidate the most suitable combination of reprogramming strategy and cell source to be applied in each human iPSC‐based therapy. The wide variety of diseases this technology could treat opens a hopeful future for regenerative medicine. Copyright

DNGR‐1+ dendritic cells are located in meningeal membrane and choroid plexus of the noninjured brain

The role and different origin of brain myeloid cells in the brain is central to understanding how the central nervous system (CNS) responds to injury. C‐type lectin receptor family 9, member A (DNGR‐1/CLEC9A) is a marker of specific DC subsets that share functional similarities, such as CD8α+DCs in lymphoid tissues and CD103+CD11blowDCs in peripheral tissues. Here, we analyzed the presence of DNGR‐1 in DCs present in the mouse brain (bDCs). Dngr‐1/Clec9a mRNA is expressed mainly in the meningeal membranes and choroid plexus (m/Ch), and its expression is enhanced by fms‐like tyrosine kinase 3 ligand (Flt3L), a cytokine involved in DC homeostasis. Using Clec9aegfp/egfp mice, we show that Flt3L induces accumulation of DNGR‐1‐EGFP+ cells in the brain m/Ch. Most of these cells also express major histocompatibility complex class II (MHCII) molecules. We also observed an increase in specific markers of cDC CD8α+ cells such as Batf‐3 and Irf‐8, but not of costimulatory molecules such as Cd80 and Cd86, indicating an immature phenotype for these bDCs in the noninjured brain. The presence of DNGR‐1 in the brain provides a potential marker for the study of this specific brain cell subset. Knowledge and targeting of brain antigen presenting cells (APCs) has implications for the fight against brain diseases such as neuroinflammation‐based neurodegenerative diseases, microbe‐induced encephalitis, and brain tumors such as gliomas. GLIA 2015;63:2231–2248

An Update on Human Stem Cell-Based Therapy in Parkinson's Disease.

CDATA[Parkinsons disease (PD) is the second most common neurodegenerative disorder after Alzheimers disease and it is characterized by the progressive loss of dopaminergic neurons of the substantia nigra pars compacta (SNpc). Current pharmacological treatments for PD are only symptomatic and unfortunately there is still no cure for this disorder. Stem cell technology has become an attractive option to investigate and treat PD. Indeed, transplantation of fetal ventral mesencephalic cells into PD brains have provided proof of concept that cell replacement therapy can be beneficial for some patients, greatly improving their motor symptoms. However, ethical and practical aspects of tissue availability limit its widespread clinical use. Hence, the need of alternative cell sources are based on the use of different types of stem cells. Stem cell-based therapies can be beneficial by acting through several mechanisms such as cell replacement, trophic actions and modulation of inflammation. Here we review recent and current remarkable clinical studies involving stem cell-based therapy for PD and provide an overview of the different types of stem cells available nowadays, their main properties and how they are developing as a possible therapy for PD treatment.

Neuronal and Glial Differentiation of Human Neural Stem Cells Is Regulated by Amyloid Precursor Protein (APP) Levels

Amyloid precursor protein (APP) is implicated in neural development as well as in the pathology of Alzheimer’s disease (AD); however, its biological function still remains unclear. It has been reported that APP stimulates the proliferation and neuronal differentiation of neural stem cells (NSCs), while other studies suggest an important effect enhancing gliogenesis in NSCs. As expected, APP protein/mRNA is detected in hNS1 cells, a model cell line of human NSCs, both under proliferation and throughout the differentiation period. To investigate the potential function that APP plays in cell fate specification and differentiation of hNS1 cells, we transiently increased human APP levels in these cells and analyzed its cell intrinsic effects. Our data indicate that increased levels of APP induce early cell cycle exit and instructively direct hNS1 cell fate towards a glial phenotype, while decreasing neuronal differentiation. Since elevated APP levels also enhanced APP intracellular domain (AICD)-immunoreactivity, these effects could be, in part, mediated by the APP/AICD system. The AICD domain can play a potential role in signal transduction by its molecular interaction with different target genes such as GSK3B, whose expression was also increased in APP-overexpressing cells that, in turn, may contribute to promoting gliogenesis and inhibiting neurogenesis in NSCs. These data suggest an important action of APP in modulating hNSCs differentiation (probably in an AICD-GSK-3β-dependent manner) and may thus be important for the future development of stem cell therapy strategies for the diseased mammalian brain.

Role of Amyloid Precursor Protein (APP) and Its Derivatives in the Biology and Cell Fate Specification of Neural Stem Cells

Amyloid precursor protein (APP) is a member of the APP family of proteins, and different enzymatic processing leads to the production of several derivatives that are shown to have distinct biological functions. APP is involved in the pathology of Alzheimer’s disease (AD), the most common neurodegenerative disorder causing dementia. Furthermore, it is believed that individuals with Down syndrome (DS) have increased APP expression, due to an extra copy of chromosome 21 (Hsa21), that contains the gene for APP. Nevertheless, the physiological function of APP remains unclear. It is known that APP plays an important role in neural growth and maturation during brain development, possibly by influencing proliferation, cell fate specification and neurogenesis of neural stem cells (NSCs). Proteolytic cleavage of APP occurs mainly via two mutually exclusive pathways, the non-amyloidogenic pathway or the amyloidogenic pathway. Other alternative pathways (η-secretase, δ-secretase and meprin pathways) have also been described for the physiological processing of APP. The different metabolites generated from these pathways, including soluble APPα (sAPPα), soluble APPβ (sAPPβ), β-amyloid (Aβ) peptides and the APP intracellular domain (AICD), have different functions determined by their structural differences, equilibrium and concentration with respect to other fragments derived from APP. This review discusses recent observations regarding possible functions of APP and its proteolytic derivatives in the biology and phenotypic specification of NSCs. This can be important for a better understanding of the pathogenesis and the development of future therapeutic applications for AD and/or DS, diseases in which alterations in neurogenesis have been described.

A Two-Dimensional Human Minilung System (Model) for Respiratory Syncytial Virus Infections

Human respiratory syncytial virus (HRSV) is a major cause of serious pediatric respiratory diseases that lacks effective vaccine or specific therapeutics. Although our understanding about HRSV biology has dramatically increased during the last decades, the need for adequate models of HRSV infection is compelling. We have generated a two-dimensional minilung from human embryonic stem cells (hESCs). The differentiation protocol yielded at least six types of lung and airway cells, although it is biased toward the generation of distal cells. We show evidence of HRSV replication in lung cells, and the induction of innate and proinflammatory responses, thus supporting its use as a model for the study of HRSV–host interactions.

Treatment of Parkinson’s disease using human stem cells

The progressive loss of dopamine neurons (DAn) in the substantia nigra is the main characteristic of Parkinson’s disease (PD), the second most common neurodegenerative disorder causing several motor symptoms. Current treatment options for PD are available to help relieve primary motor symptoms, but their longterm effectiveness is limited and they do not stop neuronal degeneration. For this reason, alternative treatment options are being sought in the form of cell replacement therapies (CRT). Several open label clinical trials involving the intrastriatal transplantation of human fetal ventral mesencephalic tissue (hfVM) has provided proof of concept that CRT could be beneficial for some patients, providing relief of motor symptoms. However, the lack of availability of tissue and ethical issues limit the clinical use on a large scale of this strategy, therefore being sought alternative cell sources, based on the use of human stem cells. In this review we provide an overview of the different types of human stem cells currently available, mainly multipotent and pluripotent stem cells, their advantages and disadvantages from an experimental and clinical point of view, and how they are being developed clinically for PD treatment. Correspondence to: Isabel Liste, Neural Regeneration Unit, Functional Unit of Chronic Disease Research. Carlos III Health Institute (ISCIII), 28220 Majadahonda, Madrid, Spain, Tel: +34 918223292; Fax: +34 918223269; E-mail: iliste@isciii.es # Equal contribution

Therapeutic Application of Stem Cell and Gene Therapy in Parkinson’s Disease

The second most common neurodegenerative disease, Parkinson’s disease (PD) is characterized by progressive loss of dopaminergic neurons which in turn causes the occurrence of several motor symptoms.

Effects of lung and airway epithelial maturation cocktail on the structure of lung bud organoids

Organoids from human pluripotent stem cells are becoming suitable models for studies of organ development, drug screening, regenerative medicine, and disease modeling. Three-dimensional minilungs in Matrigel culture have recently been generated from human embryonic stem cells. These particular organoids, named lung bud organoids, showed branching airway and early alveolar structures resembling those present in lungs from the second trimester of human gestation. We show here that the treatment of such organoids with a lung and airway epithelial maturation cocktail containing dexamethasone drives lung bud organoids to the formation of paddle-racquet like structures. This strategy may help to increase the versatility of lung organoids and to generate structures more advanced than the original branching texture.