Researches from the Institute for Bioengineering of Catalonia (IBEC), based in the Barcelona Science Park, and the University of Barcelona (UB) have achieved the creation of the first highly mature neurones from human induced pluripotent stem cells (iPSCs) using a synthetic material. The study, published in Cell Stem Cell, opens up new opportunities for the medical research and potential therapies for neurodegenerative diseases and traumatic lesions. 

The extracellular matrix is essential for the development of cells in the lab, since it provides structural support, regulates the signalling and cellular differentiation, keeps the integrity and proportionate an adequate environment for the cellular growth.

Until now, it has been possible the generation of neurons from induced pluripotent strem cells (iPSCs), but these neurones presented an insufficient maturation degree, similar to neurons in early stages of development. This limited its capacity to be used in researching neurodegenerative diseases, since it is the adult neurons that degenerate. The inefficient maturation of neurons differentiated from iPSCs was partly due to the lack of signals found in the neurons’ environment, the extracellular matrix.

To recreate the extracellular matrix and achieve a functional maturation similar to adult neurons from the nervous system in physiologic conditions, the IBEC and UB researchers used “dancing molecules”, a revolutionary technique presented this year by Dra. Zaida Álvarez from IBEC and the Prof. Samuel I. Stupp from the University of Northwestern, director of the Simpson Querrey Bionanotechnology Institute (SQI) and distinguished Severo Ochoa professor at IBEC.

“This is the first time human iPSC-derived neurons have been matured with a synthetic matrix. This platform will allow laboratories to have mature human neurons to study multiple neurological diseases and develop new therapies”, comments Dra. Álvarez, Ramón y Cajal researcher at IBEC and co-first author of the study.

The researchers believe that by advancing the age of neurons in cell cultures, experiments may be improved to better understand late-onset diseases. “Having mature neurons in the laboratory is essential to advance in the understanding of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease or amyotrophic lateral sclerosis (ALS), and in the development of effective and safe therapies”, explains Dr. Alberto Ortega, Ramón y Cajal researcher at the Faculty of Medicine and Health Sciences of the UB, member of the Institute of Neurosciences of the UB (UBneuro) and co-first author of the study.

Zaida Álvarez and Alberto Ortega (Photo: IBEC / UB).

In this new work, Zaida Álvarez and Alberto Ortega found that nanofibers with higher molecular motion led to improvements in cultures of human neurons. In other words, neurons grown on these more dynamic synthetic materials showed greater maturity, less aggregation, and more intense signalling.

“We believe that this works because receptors are moving very fast on the cell membrane and the signalling molecules of our scafolds are also moving very fast”, explained Prof. Stupp.

As part of the research, they took skin cells from an ALS patient and turned them into patient-specific motor neurons, the cell type affected in this neurodegenerative disease. These neurons were cultured for two months on the synthetic materials to develop characteristics of the ALS disease. “Not only has this provided a new window to study ALS, but this system can also be used to study and test potential therapies in other neurological diseases,” says Evangelos Kiskinis, professor of neurology and neuroscience at the Feinberg School of Medicine at the Northwestern University and Robertson Investigator at the New York Stem Cell Foundation.

Later, these highly functional neurons, thanks to the synthetic material, could be transplanted into patients with loss of neurons, due to injury or disease, which could restore lost cognition or sensations. And, because the initial cells could come from the same patient, the derived and transplanted neurons would not generate rejection.

» Reference article: Álvarez, Z.; Ortega, J. A. et al. “Artificial extracellular matrix scaffolds of mobile molecules enhance maturation of human stem cell-derived neurons”. Stem Cell Stem, January 2023. Doi: 10.1016/j.stem.2022.12.010

» More information: IBEC website [+]