New technique enables researchers to grow old human brain cells for the first time.


Aging is a major risk factor for many human diseases, and in vitro generation of human neurons is an attractive approach for modeling aging-related brain disorders.  While aggressive familial early onset versions of fatal neurodegenerative diseases like Alzheimer’s or Parkinson’s disease can emerge in mid-life, the overwhelming majority of cases develop sporadically in old age, without known genetic causes.
Neurons are a prime target for cellular aging, however, modelling aging in differentiated human neurons has yet to be achieved.  Now, researchers from Salk Institute have used skin samples from older patients to create brain cells without rolling back the youthfulness clock in the cells first.  The team state that their new technique will be a boon to scientists studying age-related diseases like Alzheimer’s and Parkinson’s as it allows cells to keep age-related signatures so that researchers can more easily study the effects of aging on the brain.  The opensource study is published in the journal Cell Stem Cell.

Previous studies show that animal models have been the go-to technique to study the biological consequences of aging, especially in tissues that can’t be easily sampled from living humans, like the brain. Over the past few years, researchers have increasingly turned to stem cells to study various diseases in humans.   Patients’ skin cells have been turned into induced pluripotent stem cells, which have the ability to become any cell in the body. From there, researchers can prompt the stem cells to turn into brain cells for further study. However, this process, even when taking skin cells from an older human, doesn’t guarantee stem cells with ‘older’ properties.  Epigenetic signatures in older cells, patterns of chemical marks on DNA that dictate what genes are expressed when, were reset to match younger signatures in the process. This made studying the aging of the human brain difficult, since researchers couldn’t create ‘old’ brain cells with the approach.  The current study directly converted skin cells to neurons, creating what’s called an induced neuron (iNs) to display age-specific transcriptional profiles and age-associated changes.

The current study used skin cells from 19 people, aged from birth to 89, and prompted them to turn into brain cells using both the induced pluripotent stem cell technique and the new direct conversion approach. The lab then compared the patterns of gene expression in the resulting neurons with cells taken from autopsied brains.

Data findings show that when the induced pluripotent stem cell method was used, as expected, the patterns in the neurons were indistinguishable between young and old derived samples. In contrast, results show brain cells that had been created using the direct conversion technique had different patterns of gene expression depending on whether they were created from young donors or older adults.  The group observed that the direct conversion technique neurons showed differences depending on donor age and actually show changes in gene expression that have been previously implicated in brain aging. The researchers explain, as an example, levels of a nuclear pore protein called RanBP17 whose decline is linked to nuclear transport defects in neurodegenerative diseases, were lower in the neurons derived from older patients.

The team surmise that by using this powerful approach, the global medical community can begin to answer many questions about the physiology and molecular machinery of human nerve cells, not just around healthy aging but pathological aging as well.  For the future, the researchers state now that the direct conversion of skin cells to neurons has been shown to retain these signatures of age they expect the technique to become a valuable tool for studying aging.

Source: Salk Institute’s Laboratory of Genetics

 

Direct Conversion of Young and Old Human Fibroblasts into Functional iNs Is Efficient Regardless of Donor Age.  Immunocytochemical characterization of iN from young and old donors after 3 weeks of conversion.  All of the scale bars represent 20 mM.  Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects.  Gage et al 2015.

Direct Conversion of Young and Old Human Fibroblasts into Functional iNs Is Efficient Regardless of Donor Age. Immunocytochemical characterization of iN from young and old donors after 3 weeks of conversion. All of the scale bars represent 20 mM. Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects. Gage et al 2015.

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