Studying and engineering muscle stem cells for myogenic cell therapies

A PhD position for the 2020 programme in the lab of Francesco Saverio Tedesco.

Project

The Tedesco lab (www.tedescolab.org) focuses on the study of skeletal muscle stem cells and regeneration and on the development of novel experimental therapies for muscle disorders. The group is interested in understanding how skeletal muscle sustains tissue regeneration and how this process could be improved to develop therapies for incurable diseases such as muscular dystrophies. Their work pioneered the engineering of human artificial chromosomes and induced pluripotent stem (iPS) cells for muscle gene and cell therapies (1-3). Recent research projects investigate the use of small molecules to improve muscle stem cell delivery (4) and the application of iPS cell-derived myogenesis for complex neuromuscular disease modelling and tissue engineering in 3D cultures (5). The overall goal of the Tedesco lab is the clinical translation of these novel regenerative strategies into therapies for muscle disorders.

This PhD project will study the development of a novel platform to study muscle stem cell migration. Muscle satellite (stem) cells are responsible for skeletal muscle regeneration. Despite their skeletal myogenic differentiation potential, satellite cells have limited migration capacity that restricts their clinical use in cell therapies for widespread forms of muscle diseases. We recently showed that modulation of Notch and PDGF pathways improve migration of mouse and human myoblasts (4). However, it is unknown if the same pathways can be exploited to modulate migration of human induced pluripotent stem (iPS) cell-derived myogenic progenitors: currently promising candidates for muscle cell therapy owing to their controllable proliferation and differentiation capacity. The candidate will therefore study if this mechanism is conserved in human iPS cell derivatives, investigating strategies to further improve it. Notably, dynamics of muscle stem cell engraftment and migration will be studied within a novel 3D platfom which will provide for the first time a humanised model to study human skeletal muscle stem cell transplantation dynamics ex vivo.

Candidate background

This project would suit candidates with theoretical and practical background in muscle stem cell biology and cell migration, and an interest in cell therapy and tissue engineering. Experience with human stem cell cultures and gene expression analysis is essential. Knowledge and experience in conducting bioinformatics analyses is desirable.

References

1.         Tedesco, F. S., Gerli, M. F., Perani, L., Benedetti, S., Ungaro, F., Cassano, M., . . . Cossu, G. (2012)

            Transplantation of genetically corrected human iPSC-derived progenitors in mice with limb-girdle muscular dystrophy.

            Science Translational Medicine 4: 140ra189. PubMed abstract

2.         Maffioletti, S. M., Gerli, M. F., Ragazzi, M., Dastidar, S., Benedetti, S., Loperfido, M., . . . Tedesco, F. S. (2015)

            Efficient derivation and inducible differentiation of expandable skeletal myogenic cells from human ES and patient-specific iPS cells.

            Nature Protocols 10: 941-958. PubMed abstract

3.         Benedetti, S., Uno, N., Hoshiya, H., Ragazzi, M., Ferrari, G., Kazuki, Y., . . . Tedesco, F. S. (2018)

            Reversible immortalisation enables genetic correction of human muscle progenitors and engineering of next-generation human artificial chromosomes for Duchenne muscular dystrophy.

            EMBO Molecular Medicine 10: 254-275. PubMed abstract

4.         Gerli, M. F. M., Moyle, L. A., Benedetti, S., Ferrari, G., Ucuncu, E., Ragazzi, M., . . . Tedesco, F. S. (2019)

            Combined Notch and PDGF Signaling Enhances Migration and Expression of Stem Cell Markers while Inducing Perivascular Cell Features in Muscle Satellite Cells.

            Stem Cell Reports 12: 461-473. PubMed abstract

5.         Maffioletti, S. M., Sarcar, S., Henderson, A. B. H., Mannhardt, I., Pinton, L., Moyle, L. A., . . . Tedesco, F. S. (2018)

            Three-dimensional human iPSC-derived artificial skeletal muscles model muscular dystrophies and enable multilineage tissue engineering.

            Cell Reports 23: 899-908. PubMed abstract