CENTRO DE BIOLOGÍA MOLECULAR SEVERO OCHOA

Biology of human neural stem cells. Potential for cell and gene therapy in neurodegeneration

Research summary:

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.

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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

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Last nameNameLaboratoryExt.*e-mailProfessional category
García LópezSilvia3054650sglopez(at)cbm.csic.esTitulado Superior Grado de Doctor
Martínez SerranoAlberto3054620amserrano(at)cbm.csic.esProfesor Titular Universidad, GA
Pérez PereiraMarta3054650pereiram(at)cbm.csic.esProfesor Ayudante Doctor Universidad
Rodríguez RubioMarina3054650marina.rodriguez(at)cbm.csic.esTitulado Sup.de Actividades Técn. y Profes. GP1
Stancic Brina3054650bstancic(at)cbm.csic.esTco. de Investigación y Laboratorio

Relevant publications:

  • Sánchez-González C, Nuevo-Tapioles C, Herrero Martín JC, Pereira MP, Serrano Sanz S, Ramírez de Molina A, Cuezva JM and Formentini L. (2020) Dysfunctional oxidative phosphorylation shunts branched-chain amino acid catabolism onto lipogenesis in skeletal muscle. EMBO J.;39(14):e103812. https://doi.org/10.15252/embj.2019103812.

 

  • Okarmus J, Bogetofte H, Schmidt SI, Ryding M, García-López S, Ryan BJ, Martínez-Serrano A, Hyttel P, and Meyer M. (2020). Lysosomal perturbations in human dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation. Sci Rep. 10(1):10278. https://doi.org/10.1038/s41598-020-67091-6.
  • Kajtez J, Buchmann S, Vasudevan S, Birtele M, Rocchetti S, Pless CJ, Heiskanen A, Martinez-Serrano A, Parmar M, Lind JU and Emnéus J. (2020). 3D-Printed soft lithography for complex compartmentalized microfluidic neural devices. Adv Sci (Weinh);7(16):2001150. https://doi.org/10.1002/advs.202001150.
  • Asif A, García-López S, Heiskanen A, Martínez-Serrano A, Keller SS, Pereira MP and Emnéus J. (2020) Pyrolytic carbon nanograss enhances neurogenesis and dopaminergic differentiation of human midbrain neural stem cells. Advanced Healthcare Materials 9, n.o 20: e2001108. https://doi.org/10.1002/adhm.202001108.
  • Vasudevan S, Kajtez J, Bunea A-I, Gonzalez-Ramos A, Ramos-Moreno T, Heiskanen A, Kokaia M, Larsen NB, Martínez-Serrano A, Keller SS and Emnéus J (2019). Leaky optoelectrical fiber for optogenetic stimulation and electrochemical detection of dopamine exocytosis from human dopaminergic neurons. Adv Sci (Weinh). 6(24):1902011. https://doi.org/10.1002/advs.201902011
  • Rothenbücher TSP, Martínez-Serrano A. Human cerebral organoids and neural 3D tissues in basic research, and their application to study neurological diseases. (2019) Future Neurology.14(1):FNL3. https://doi.org/10.2217/fnl-2018-0043
  • Martín-Hernández D, Pereira MP, Tendilla-Beltrán H, Madrigal JLM, García-Bueno B, Leza JC and Caso JR (2019). Modulation of monoaminergic systems by antidepressants in the frontal cortex of rats after chronic mild stress exposure. Mol Neurobiol. 56(11):7522-33. DOI: 10.1007/s12035-019-1619-x
  • Hey SM, Jensen P, Ryding M, Martínez Serrano A, Kristensen BW, Meyer M. (2019). Nonhypoxic pharmacological stabilization of Hypoxia Inducible Factor 1α: Effects on dopaminergic differentiation of human neural stem cells Eur J Neurosci. 49(4):497-509. DOI: 10.1111/ejn.14284
  • Coronel R, Lachgar M, Bernabeu-Zornoza A, Palmer C, Domínguez-Alvaro M, Revilla A, Ocaña I, Fernández A, Martínez-Serrano A, Cano E and Liste I. (2019) Neuronal and glial differentiation of human neural stem cells is regulated by Amyloid Precursor Protein (APP) Levels Mol Neurobiol.56(2):1248-61. DOI: 10.1007/s12035-018-1167-9
  • Bernabeu-Zornoza A, Coronel R, Palmer C, Calero M, Martínez-Serrano A, Cano E, Zambrano A and Liste I. (2019) Aβ42 peptide promotes proliferation and gliogenesis in human neural stem cells Mol Neurobiol. 56(6):4023-36. DOI: 10.1007/s12035-018-1355-7

Doctoral theses:

  • Theresa SP Rothenbücher (2020) “Engineered brain organoids. Developing an improved and larger human brain model in vitro”
  • Anna Nelke (2019) “Differential effects of neural stem cell therapy in adult and middle-aged Parkinsonian mice”
  • 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.
  • Emma Green (2012). The use of zinc-finger nucleases to track the generation of dopaminergic neurons from immortalised human ventral mesencephalic neural stem cells. Universidad de Keele. Co-directores: Alberto Martínez Serrano y Tania Ramos Moreno.

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