How Are Stem Cells Used in Autism Research?

Research Advances > Stem Cells > Stem cell research in autism

The organ affected in Autism Spectrum Disorders (ASD) is the brain. Before stem cell technologies existed, brain studies had to be done in post-mortem tissue or in other animals. Neither of these approaches are ideal for understanding what is happening in a human patient. Advances in stem cell technology, however, have provided researchers with the means to study functional brain cells from living autistic patients.

iPSCs offer an unique opportunity to address some of the key issues in the field of ASD research, such as whether the clinical severity of ASD in an autistic patient correlates with the magnitude of phenotype in iPSC-derived cells from that patient¹. Furthermore, the ability to generate patient-specific neurons and other brain cells provides us with the opportunity to potentially develop individualized therapies. The information obtained about the drug response by iPSC-derived neurons from an autistic patient can potentially be used to predict the clinical pharmacological response in that patient.

Click here to learn other methods for generating patient-specific brain cells

In addition to deriving them from induced pluripotent stem cells, there are additional techniques available to generate patient-specific brain cells, although these approaches have their own advantages and drawbacks. Recent studies have found that human fibroblasts can be directly converted into functional neurons (also known as iNeurons), thereby completely bypassing the intermediate step of first converting somatic cells to induced pluripotent stem cells^2-6. This process is fairly rapid and relatively efficient compared to similar conversions from iPSCs. However, because these cells lack the capability for self-renewal, large numbers of fibroblasts from a patient would be required to generate a sufficient number of neurons for study¹. Furthermore, it is unknown if, by directly converting somatic cells to neurons, the cellular phenotype of neurodevelopmental disorders such as ASD will be “shortcut” by bypassing potentially critical steps of neuronal differentiation and maturation. As a result, any potential defects in differentiation and maturation that occurred in neurons from ASD patients will be missed in iNeurons from the same patient. Olfactory neural stem cells, which can be removed by non-invasive methods from the olfactory mucosa, are another potential source. These stem cells are capable of self-renewal and can also be differentiated into functional neurons⁷. However, it is unknown if neurons derived from the olfactory mucosa will show the types of functional defects expected from neurons in areas of the brain affected by ASD⁸. A recent article reported the direct reprogramming of human fibroblasts into induced neural stem cells (iNSCs), which were capable of differentiating into mature neurons, astrocytes, and oligodendrocytes⁹. The table below summarizes the pros and cons of the techniques available to generate patient-specific cells.

Source of patient-specific cells	Pros	Cons
Induced pluripotent stem cells (iPSCs)	Well-established technique Able to generate specific neural lineages of interest, such as glutamatergic neurons Able to generate glial cells (astrocytes and oilgodendrocytes)	Neuron-to-neuron variability Variability between iPSC lines from a single patient Patient-to-patient variability Low efficiency of conversion (typically less than 1%) Time course required ~5-6 weeks required for iPSCs to be differentiated into neurons ~12 weeks required for iPSCs to be differentiated into astrocytes ~15 weeks required for iPSCs to be differentiated into oligodendrocytes
iNeurons (direct conversion of fibroblasts into neurons)	Capable of generating functional neurons Relatively efficient conversion to neurons (1.8-7.7%) Rapid process (functional neurons within 2 weeks)	No inherent capacity for self-renewal Large numbers of patient-derived fibroblasts required Unknown if bypassing differentiation step will “shortcut” cellular phenotypes
Olfactory neural stem cells (ONSCs)	Capable of self-renewal and differentitation into functional neurons Non-invasive source of cells	Unknown if neurons derived from these cells can recapitulate all neuronal defects present in specific brain regions (cortex, hippocampus) Cannot yet be used as a source of cells from certain neural lineages of interest (dopaminergic neurons, glutamatergic neurons, etc.)
iNSCs (conversion of fibroblasts into neural stem cells)	Rapid process (compared to iPSCs) Ability to self-renew (an inability that iNeurons lack) Ability to differentiate into neurons, astrocytes, and oligodendrocytes Do not generate tumors (unlike iPSC-derived neural stem cells)	Limited self-renewal (compared to iPSCs)

Thus far, research has primarily focused on examination of patient-specific neurons derived from induced pluripotent stem cells. However, future research will likely include examination of patient-specific non-neuronal brain cell types, such as astrocytes and oligodendrocytes. Both of these cell types are required for optimal neuronal function; astrocytes function as a support system for neurons, while oligodendrocytes are responsible for the myelin sheathes that surrounds and insulates the axons of neurons. Given recent observations that demonstrate the importance of astrocytes in mouse models of Rett syndrome, more attention will be paid to the possible clinical importance of astrocytes and oligodendrocytes in ASD. Likewise, other potential sources of patient-specific cells have been explored, as described in greater detail below.

Induced pluripotent cells

ASD Findings from Stem Cells

References:

Brennand KJ, Gage FH (2012) Modeling psychiatric disorders through programming. Dis. Model Mech. 5(1): 26-32. PMID: 21954066.
Pang Z, et al. (2011) Induction of human neuronal cells by defined transcription factors. Nature 476(7359): 220-223. PMID: 21617644.
Pfisterer U, et al. (2011) Direct conversion of human fibroblasts to dopaminergic neurons. Proc. Natl. Acad. Sci. U.S.A. 108(25): 10343-10348. PMID: 21646515.
Caiazzo M, et al. (2011) Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476 (7359): 224-227. PMID: 21725324.
Yoo AS, et al. (2011) MicroRNA-mediated conversion of human fibroblasts to neurons. Nature 476(7359): 228-31. PMID: 21753754.
Ambasudhan R, et al. (2011) Direct reprogramming of adult human fibroblasts to functional neurons under defined conditions. Cell Stem Cell 9(2): 113-118. PMID: 21802386.
Matigian N, et al. (2010) Disease-specific, neurosphere-derived cells as models for brain disorders. Dis. Model Mech. 3(11-12): 785-798. PMID: 20699480.
Brennand KJ, Gage FH (2011) Concise review: the promise of human induced pluripotent stem cell-based studies of schizophrenia. Stem Cells 29(12): 1915-1922. PMID: 22009633.
Ring KL, et al. (2012) Direct reprogramming of mouse and human fibroblasts into multipotent neural stem cells with a single factor. Cell Stem Cell. PMID: 22683203.

How Are Stem Cells Used in Autism Research?

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