Biology of human neural stem cells. Potential for cell and gene therapy in neurodegeneration
The concept of treating diseases with replacement cells in not new; blood transfusions, skin grafts and organ transplantation are all forms of cell replacement therapy. Many neurological diseases, like PD, are the result of cell death or degeneration. The exponentially growing impairment/death rate of dopaminergic neurons (DAn) in the midbrain’s substantia nigra (the A9 subgroup) in PD limits the therapeutic window of the treatments available that are known to increase the quality of life of patients although none can prevent the progression of PD.
Consequently, repairing damaged tissue becomes the goal; when cell loss cannot be prevented, cell replacement holds the key to recovery. Cell replacement therapy for PD is based on the concept that DAn implanted ectopically may functionally restore and maintain the DA levels lost in the disease. Clinical research using human fresh fetal ventral mesencephalic (VM) tissue (hfVM, containing some DAn precursors and many other cell types) provided proof of principle of the therapeutic efficacy of dopaminergic transplants on a long-term basis. However, limitations in hfVM supply, along with the variability of results of different clinical trials and the appearance of graft-induced dyskinesias in some patients, have precluded the implantation of tissue transplantation as a clinical therapy. In this context, research on the basic biology of human stem cells acquires special relevance. Our research group is interested in the basic biology of stem cells and the developmental events leading to maturation of neuronal derivatives of use in the study of the human brain and the development of novel cell-based therapies for neurodegenerative diseases (e.g. Parkinson’s and Alzheimer’s disease).
We have studied the trophic actions of human neural and mesenchymal stem cells in experimental in vivo models of PD focusing on the parallelism between pathological changes occurring in the brain vs. neurological and motor alterations. With a multidisdisciplinary approach, we have worked in the development of the technology for externally controllable bioimplants of therapeutic cells on-demand. These bioimplants consisting in multifunctional leaky optoelectrical fiber for potential neuromodulation and as a cell substrate for application in combined optogenetic stem cell therapy.
With the aim of minimizing the number of laboratory animals used for basic research while increasing the body of knowledge on the biology human neural tissue we have developed a research line devoted to the generation of human cerebral organoids with improved features facilitating patterning studies and useful for improving current preclinical research testing.
FIGURE 1: Transplantation of ventral mesencephalic hNSCs in adult (5 mo-old) and middle-aged (12 mo-old) PD mice (MPTP lesion).
Coronal sections of the mouse brain (4 mo post transplantation) immunostained for tyrosine hydroxylase (a marker of dopaminergic neurons and their projections) at the level of rostral and caudal striatum (upper panels) and substantia nigra (lower panels). Control are intact animals, whereas Buffer and Cell correspond to MPTP-lesioned animals receiving either buffer injection or cell suspension. IL (ipsilateral) = hemisphere receiving buffer or cells. CL (contralateral) = hemisphere opposite to transplantation. Tyrosine hydroxylase fiber loss in the striatum and DAn loss in the SNpc of adult mice was prevented by stem cell transplantation, while TH neurodegeneration in middle-aged mice was prevented only in the SNpc and not the striatum
|Last name||Name||Laboratory||Ext.*||Professional category|
|Pérez Pereira||Marta||305||4650||pereiram(at)cbm.csic.es||Profesor Ayudante Doctor Universidad|
|Rodríguez Rubio||Marina||305||4650||marina.rodriguez(at)cbm.csic.es||Titulado Sup.de Actividades Técn. y Profes. GP1|
|Stancic||Brina||305||4650||bstancic(at)cbm.csic.es||Tco. de Investigación y Laboratorio|
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- Javier Gonzalez Lendínez (2011). Identification and analysis of suitable human ventral mesencephalic precursors of dopaminergic neurons for cell therapy research in Parkinson's Disease. Universidad Autónoma de Madrid. Co-director: Dra. Tania Ramos Moreno.
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