Scientists from the Institute of Bioengineering of Catalonia (IBEC) and the University of Barcelona (UB) have managed to create the first highly mature neurons from human-induced pluripotent stem cells (iPSCs) using a synthetic material, opening up new opportunities for medical research and potential therapies for neurodegenerative diseases and traumatic injuries. The results are published in the journal Cell Stem Cell.
“This is the first time that iPSC-derived human 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 co-author Zaida Álvarez, Ramón y Cajal researcher at IBEC.
Neurons derived from human induced pluripotent stem cells (iPSC) were matured with a synthetic matrix, which will allow the study of multiple neurological diseases and the development of new therapies
Until now, it was possible to generate neurons from induced pluripotent stem cells, but these neurons showed an insufficient degree of functional maturity, similar to that of neurons in early stages of development. This has limited their ability to investigate neurodegenerative diseases, as it is the adult neurons that degenerate.
The inefficient maturation of neurons differentiated from iPSCs was due in part to the lack of signals found in the neurons’ environment, the extracellular matrix.
In this context, the extracellular matrix is essential for cell development in the laboratory, as it provides structural support, regulates cell signaling and differentiation, maintains cell integrity and provides a suitable environment for cell growth.
The “dancing molecules” technique
To recreate the extracellular matrix and achieve maturation and functionality similar to neurons in the nervous system under physiological conditions, the researchers used “dancing molecules”, a revolutionary technique presented last year by researchers Zaida Álvarez, from IBEC, and Samuel I. Stupp, from Northwestern University (USA).
The first step was to differentiate the human iPSCs into motor and cortical neurons and then place them in nanofibers composed of “dancing molecules”, where the researchers observed that the signaling and branching capacity of the neurons had improved, allowing them to generate better cells. synaptic contacts with each other.
As neurons age in cell cultures, experiments can be improved to better understand late-onset diseases.
The researchers believe that by advancing the age of neurons in cell cultures, experiments can 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, Parkinson’s or amyotrophic lateral sclerosis (ALS), and in the development of effective and safe therapies”, comments another of the authors, Alberto Ortega, researcher Ramón y Cajal from the UB.
To grow the mature neurons, the researchers used nanofibers composed of “dancing molecules,” a material that Zaida Álvarez developed in Stupp’s laboratory as a potential treatment for acute spinal cord injuries.
In previous research published in the journal Science, the researcher discovered how to change the movement of molecules so that they can find and connect more efficiently to cell receptors that are in constant motion.
Enhanced neuron cultures
In the new study, Zaida Álvarez and Alberto Ortega found that nanofibers with greater molecular motion led to improvements in cultures of human neurons. In other words, neurons grown in these more dynamic synthetic materials showed greater maturity, less aggregation, and stronger signaling.
“We think this works because the receptors move very fast in the cell membrane and the signaling molecules in our scaffolds also move very fast,” explains Stupp, director of the Simpson Querrey Institute for BioNanotechnology (SQI) and Severo Ochoa Distinguished Professor at IBEC .
Skin cells were taken from an ALS patient and transformed into patient-specific motor neurons, which were then cultured to develop characteristics of the disease.
As part of the research, they took skin cells from a patient with ALS and turned them into patient-specific motor neurons, the type of cell affected in this neurodegenerative disease. These neurons were cultured for two months in the synthetic materials to develop disease features of ALS.
“Not only has this provided a new window to study ALS, but it 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 Northwestern University. and Robertson Investigator of the New York Stem Cell Foundation.
Hopes for future treatments
Later, these highly functional neurons, thanks to the synthetic material, could be transplanted into patients with neuron loss, due to spinal cord injury or disease, which could restore lost cognition or sensations.
Furthermore, as the initial cells could come from the same patient, the derived and transplanted neurons would not generate rejection.
The Artificial Extracellular Matrix Scaffolds of Mobile Molecules Enhance the Maturation of Human Stem Cell-Derived Neurons study, which also included Kohei Sato of Tokyo Institute of Technology, Japan and Elisabeth Engel of IBEC, received funding from various entities.
Specifically: Ministry of Science, Government of Spain, Mike Lane de Castellers de Vila de Gracia Scholarship 2021, Springboard AFM-Telethon, Beatriu de Pinos 2019, Ramon y Cajal Scholarship, Center for Regenerative Nanomedicine of the Simpson Querrey Institute of BioNanotechnology, National National Institute Institutes of Health (NIH) Neurological Disorders and Stroke, NIH National Institute on Aging, NIH National Institute of Biomedical Sciences Imaging and Bioengineers, NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases, Les Turner ALS Foundation, New York Stem Cell Foundation, Department of Energy and the Paralyzed American Veterans Research Foundation.