Last August, the cover of the prestigious journal Cell Stem Cell, was dedicated to a pioneering discovery made by two independent groups that obtained functional neuron cells from human and mouse fibroblasts cultured with a cocktail of several small molecules. This finding may position these Chinese researchers at the cutting edge of translational and regenerative medicine.
From fibroblast to neuron
Dr. Hongkui Deng from Peking University and Dr. Gang Pei from University of Chinese Academy of Sciences in Shanghai, achieved almost the same conclusions, when they started to investigate whether it was feasible to “transform” a fibroblastic cell into a neuron, without the use of any genetic interference. The main difference, apart from the chemical agents that composed the cocktails they used, was that the group from Peking started from mouse cells, whereas Pei and colleagues used cells from a 28-year-old male. They both concluded that several factors were necessary but no sufficient to induce the reprogramming of a fibroblast toward a neuron and that the combinations of different molecules was the key. Indeed, some of them were central to turn off genes normally expressed in fibroblasts and others were required to induce the expression of neuronal specific genes.
The switch process was very fast and did not apparently pass through the generation of intermediate cell populations or neuron precursors. Actually, after a few days the authors obtained the full conversion of fibroblasts into long lasting functional neurons able to form synaptic connections with each other or with primary neurons. Interestingly, both groups also observed that most of the neurons were glutamatergic and a smaller fraction GABAergic, while no considerable cholinergic or dopaminergic neurons were obtained.
Dr. Pei’s group also isolated fibroblasts from patients with familial Alzheimer’s disease and cultured them with the chemical cocktail, successfully obtaining patient-specific neuronal cells. It cannot be excluded that minor modifications to the differentiation cocktails used by the two groups may lead in the future to the generation of other types of neurons.
What are the real meaning and novelty of this discovery?
First, it tells us that even fully differentiated cells such as fibroblasts can still reprogram into completely different cells and have more plasticity than we thought. Second, the possibility of obtaining functional neurons from fibroblasts will permit researchers to investigate the impaired neuronal functions in pediatric and adult patients affected by genetic or acquired neurological disorders. Finally, in these studies only small compounds were used to directly reprogramming one cell lineage into another. Previous works aimed to reprogram somatic cells usually made use of insertion of genetic material into the cell of origin, in order to push its differentiation toward another cell. These latter strategies are normally less effective and safe.
“In comparison with using transgenic reprogramming factors, the small molecules that are used in this chemical approach are cell permeable; cost-effective; and easy to synthesize, preserve, and standardize; and their effects can be reversible,” says Dr. Deng “In addition, the use of small molecules can be fine-tuned by adjusting their concentrations and duration, and the approach bypasses the technical challenges and safety concerns of genetic manipulations”.
Cell therapy for inborn errors of metabolism
Nowadays, nobody knows whether this discovery will be useful for the treatment of inherited neurometabolic disorders (INMDs), rare genetic conditions that are usually caused by the lack of an enzyme essential to normal metabolism. Indeed, the administration of mature cells that express a functional enzyme might help in restoring or ameliorating normal brain function. So far, a similar strategy has been adopted by clinicians for the treatment of young patients suffering from INMDs such as mucopolysaccharidoses, adrenoleukodystrophy, metachromatic leukodystrophy and globoid leukodystrophy. In these settings, hematopoietic stem cell transplantation (HSCT), that is the transfer to the patients of undifferentiated cells coming from bone marrow, peripheral blood or cord blood, has given encouraging results. The scientific basis of HSCT is that, once in the recipient, stem cell can differentiate into mature cells and provide the missing enzyme. In particular, it has been show that they can give origin to microglias (the brain glial cells) when they reach the brain.
However, this therapy present some important limitations. The principal is that patients have to wait about nine months before seeing an effect, that is the time needed to stem cells to engraft the host and differentiate. This means that transplant cannot repair the damage already present or that will occur from the beginning of treatment until the cells differentiate. For this reason, often HSCT is not a cure, but a way to ameliorate patient’s suffering. Implementation of newborn screening for INMDs is thus essential to identify and treat patients at risk before irreversible organ damage occurs. In addition, HSCT is still associated to a high risk of morbidity and mortality.
On the other hand, HSCT presents many advantages compared to the exogenous enzyme replacement therapy (ERT), the alternative treatment option to provide the missing enzyme. In fact, ERT is available only for a limited number of disorders like mucopolysaccharidoses, Fabry, Gaucher and Pompe disease, it cannot cross the blood-brain barrier and long-term ERT can occur with hypersensitivity reactions. From 1980, when the first HSCT was performed in a patient with Hurler syndrome, more than thousand transplants have been realized throughout the world. Although the short-term impact of HSCT on clinical outcome seems to be favorable, there are still few available data on the follow-up of transplanted patients.
Researchers can now obtain functional neuron cells by culturing fibroblasts with a cocktail of differentiating chemical compounds.
Obtaining brain cells through the differentiation of unrelated cells is a promising strategy already used in the treatment of pediatric patients affected by certain inborn errors of metabolism.
Hu W. et al. Direct Conversion of Normal and Alzheimer’s Disease Human Fibroblasts into Neuronal Cells by Small Molecules. Cell Stem Cell. 2015 Aug 6;17(2):204-12.
Li X. et al. Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons. Cell Stem Cell. 2015. Aug 6;17(2):195-203.