Massimiliano Caiazzo started his studies in Naples at the Institute of Genetics and Biophysics, CNR, “A. Buzzati-Traverso” and at CE.IN.GE. Biotecnologie Avanzate where he was involved in the study of the role of the transcription factors that drive induction and differentiation of midbrain dopaminergic neurons that are crucial in the pathogenesis of Parkinson’s disease (PD).
During his PhD he started to be interested in the field of embryonic and neural stem cells that led him to an internship at Montreal Neurological Institute (McGill University, Montreal) and subsequently at hospital San Raffaele in Milano where he performed pioneering studies in the field of cell reprogramming and transdifferentiation. He finally completed his training at EPFL in the Laboratory of Stem Cell and Bioengineering where he combined the use of 3D hydrogels to cell reprogramming and organogenesis.
In 2016 he moved to Utrecht University as assistant professor to start his own research lines focused on cell therapies.
Caiazzo group research is focused on regenerative medicine in the field of neurobiology. His basic aim is to combine cell reprogramming and the modulation of cell microenvironmental parameters in order to generate human neural cells for cell replacement and disease modeling. To date the study of pathological dynamics in neurodegenerative diseases is linked to the use of animal models that cannot recapitulate the complexity and sensitivity of the human brain. On the other side we have the chance to study human neurons only as single cell population in a cell culture dish. Therefore his long-term goal is to generate complex in vitro human neural systems that can simulate the functionality of neuronal pathways and their interactions with different neural populations such as astrocytes, microglia and oligodendrocytes. The achievement of human neural models with higher degree of complexity will be instrumental to understand and characterize the early steps of neurodegenerative diseases such as PD. This approach can eventually lead to the identification of new early diagnostic and therapeutic targets and therefore to a new powerful tool to perform drug screening approaches.
The three main ongoing projects in Caiazzo group are the following:
1) Identification of micro-RNA (miRNA) involved in dopaminergic (DA) neuronal transdifferentiation
Direct conversion of somatic cells into dopaminergic neurons can be achieved by forcing the expression of the DA transcription factors Ascl1, Nurr1 and Lmx1a (Caiazzo et al 2011, Dell’Anno et al., 2014). Nevertheless this process is still highly inefficient in adult human cells, leading to immature neurons. In order to identify transcriptional regulators of neuronal reprogramming, Caiazzo group aims to screen the mirnome profile of cells undergoing transdifferentiation. This experimental approach will eventually lead to the identification of molecular roadblocks in the reprogramming of adult human cells, therefore leading to an increase in the efficiency of the direct conversion technology and to an improved maturation of human reprogrammed DA neurons.
2) Generation of a human model of nigrostriatal pathway
PD is associated with the degeneration of the nigrostriatal pathway that is constituted by a cluster of mesencephalic (mDA) neurons (known as A9 nucleus) projecting to GABAergic medium spiny neurons of the caudate-putamen. The degeneration of this pathway leads to severe movement control dysfunctions that are the main cause of disability in PD. Our current knowledge of PD-associated neurodegeneration in humans is mainly linked to post-mortem brain tissue analysis. In order to better understand PD neurodegenerative dynamics, Caiazzo group aims to generate a model of human nigrostriatal pathway combining the use of hiPSCs with 3D culture in defined microenvironments. To this aim we will embed hiPSCs in tunable 3D-PEG hydrogels and differentiate them either in mDA neurons or GABAergic medium spiny neurons. Therefore in order to induce mDA neurons to project towards their natural GABAergic target we will engineer the target 3D-PEG hydrogel with DA axon-pathfinding molecules. In a second step this approach will then be used starting from PD-patient-derived cells in order to elucidate the dynamics of nigrostriatal neurodegeneration in a completely human PD model. Proteomic and transcriptomic analysis will help to identify early molecular markers of neurodegeneration, leading potentially to the discovery of new targets for the early treatment of PD and to new early diagnostic parameters.
3) Generation of reprogrammed astrocytes to treat neurodegenerative diseases
Astrocytes are the main cell type in the brain and it is known that their functional impairment contributes to neuronal dysfunction in several neurodegenerative diseases. However, so far, astrocyte transplantation is still unexplored as approach to treat the diseased brain. To this aim, we will use astrocytes directly converted from skin cells (Caiazzo et al., 2015) and test their therapeutic potential after brain transplantation for the treatment of lysosomal storage disorders (LSDs) and PD. LSDs are a group of over 50 inherited pediatric diseases due to enzymatic dysregulation leading to dysfunctions in the clearance of cellular waste products. To date, no cures have been developed to treat the progressive neurodegeneration caused by LSDs. Since lysosomal enzymes are secreted and uptaken by the cells we will exploit this biological feature for therapeutic purposes and use the transplanted astrocytes as an in situ factory for the production of the missing enzyme in the host brain. Our goal is to genetically correct skin cells isolated from LSD patients and then to differentiate them into astrocytes and transplant into the brain of LSD mouse models to test their therapeutic potential. Moreover we plan to use the same reprogramming approach to investigate the possible use of reprogrammed astrocytes in order to treat PD. The proposed project will show that the use of astrocytes derived from skin fibroblasts has strong potential to open new avenues for the treatment of many neurodegenerative disorders.
- Caiazzo M., Okawa Y., Ranga A., Piersigilli A., Tabata Y., Lutolf M.P. Defined 3D microenvironments boost induction of pluripotent stem cells. Nat. Materials, 2016; 15(3):344-352
- Caiazzo M., Giannelli S., Valente P., Lignani G., Carissimo A., Sessa A., Colasante G., Bartolomeo R., Ferroni S., Settembre C., Benfenati F., Broccoli V. Direct conversion of fibroblasts into functional astrocytes by defined transcription factors. Stem Cell Reports, 2015; 13;4(1):25-36
- Dell’Anno M.T., Caiazzo M., Leo D., Dvoretskova E., Medrihan L., Giannelli S., Theka I., Russo G., Mus L., Pezzoli G., Gainetdinov R.R., Benfenati F., Taverna S., Dityatev A., Broccoli V., Remote control of induced dopaminergic neurons in parkinsonian rats. J. Clin. Invest. 2014; 124(7):3215-3229
- Caiazzo M., Dell’Anno M.T., Dvoretskova E., Lazarevic D., Taverna S., Leo D., Sotnikova T., Menegon A., Roncaglia P., Russo G., Colciago G., Carninci P., Pezzoli G., Gainetdinov R.R., Gustincich S., Dityatev A., Broccoli V., Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 2011; 476(7359):224-227.