More Avenues of Hope for Damaged Brains
Induced Neurogenesis for Research and Regeneration
Researchers have discovered two ways to create neurons from a person’s own skin cells: The first way is by creating induced pluripotent stem cells, which are then stepwise converted to neurons. The second way, more recently devised, is to convert skin cells to neurons directly (induced neurons — iNs), bypassing the stem cell conversions.
The earlier process — induced pluripotent stem cells (iPSCs), may be more valuable to regenerative medicine. The more recent process — direct conversion to neurons — is likely to be more immediately valuable to researchers who are studying brain diseases such as Alzheimer’s, Parkinson’s, Huntington’s, multiple sclerosis, brain cancers, and other destructive and degenerative diseases of the nervous systems.
Induced pluripotent stem cells (iPSCs) generated from human fibroblasts can be coaxed into a plethora of different cell types, including neurons. Researchers have used them to study genetic and cellular factors that underlie age-related neurodegenerative diseases, including AD (see Mar 2015 news; Jan 2012 news; Aug 2012 conference news). The hope is that neurons derived from patients who carry disease-associated genetic variants will reveal something about disease mechanisms. However, the influence of age, the major risk factor for AD, may be lost when fibroblasts are converted to the embryo-like iPSCs (see Vera and Studer, 2015; Studer et al., 2015). Indeed, researchers have reported that iPSCs from centenarians have the telomere size, mitochondrial metabolism, and gene-expression profiles of embryonic stem cells …
In recent years, using the right mix of transcription factors and small molecules, researchers directly converted fibroblasts into functional neurons, all without a single cell division step (see Jan 2010 news; Pang et al., 2011; and Ladewig et al., 2012).
First author Jerome Mertens and colleagues wanted to produce neurons more representative of the donor’s age. They first set out to determine whether iPSCs were indeed freed from the shackles of aging. They generated fibroblast lines from 19 donors ranging in age from birth to 89 years, and derived iPSCs from 16 of them. They used RNA sequencing to analyze the gene-expression profiles of both the fibroblasts and resulting iPSCs. The researchers found that 78 genes from fibroblasts were differentially expressed between donors younger or older than 40 years of age. However, this age-related genetic signature was virtually wiped out in iPSCs, which only had one differentially expressed gene between older versus younger donors.
The researchers next directly converted the fibroblasts into neurons using established protocols. Strikingly, they found 202 genes differentially expressed between the older (>40) and younger (<40) age groups. Both fibroblasts and iNs had a subset of genes that progressively changed expression with age. Interestingly, these age-related genes in the fibroblasts were almost entirely different to those in the iNs: only seven genes overlapped. This indicated that each cell type had its own aging signature. Indeed, expression of genes related to important skin functions such as wound healing and stress responses changed in old versus young fibroblasts, while for iNs it was genes involved in processes such as calcium homeostasis, neuronal morphology, and synaptic plasticity.
…. Age-related expression patterns of only three genes—LAMA3, PCDH10, and RANBP17—overlapped in fibroblasts, iNs, and cortical samples. The researchers reasoned that such common genes could represent master regulators of aging that occurred across cell types. They focused on RanBP17 due to its provocative function. As a member of the importin-β family, RanBP17 forms part of the nuclear pore complex that helps shuttle properly tagged proteins from the cytoplasm into the nucleus. The researchers reported that levels of RanBP17 protein decreased with age in both the iNs and fibroblasts. These findings jibed with a slew of cancer studies that reported RanBP17 among the top age-related genes.
Natural Neurogenesis in Mammalian Brains
New neurons in our brains may help us to remember new experiences — and help us to forget older experiences!
Last year, for example, neuroscientist Paul Frankland of the Hospital for Sick Children in Toronto and his colleagues found evidence that newly generated neurons play a role in forgetting, with increased neurogenesis resulting in greater forgetfulness among mice.9 “If you think about what you’ve done today, you can probably remember in a great deal of detail,” he says. “But if you go back a week or if you go back a month, unless something extraordinary happened, you probably won’t remember those everyday details. So there’s a constant sort of wiping of the slate.” New hippocampal neurons may serve as the “wiper,” he says, “cleaning out old information that, with time, becomes less relevant.”
Conversely, Frankland’s team found, suppressing neurogenesis seems to reinforce memories, making them difficult to unlearn. “We think that neurogenesis provides a way, a mechanism of living in the moment, if you like,” he says. “It clears out old memories and helps form new memories.”
… The birth of new neurons in the adult hippocampus may also influence the development and progression of mood disorders. Several studies have suggested that reduced neurogenesis may be involved in depression, for instance, and have revealed evidence that antidepressants act, in part, by promoting neurogenesis in the hippocampus. When Columbia University’s René Hen and colleagues short-circuited neurogenesis in mice, the animals no longer responded to the antidepressant fluoxetine.10 “It was a very big surprise,” Hen says. “The hippocampus has really been always thought of as critical for learning and memory, and it is, but we still don’t understand well the connection to mood.”
… If new neurons are not being formed in the hippocampus, a person suffering from PTSD may be less able to distinguish a new experience from the traumatic one that is at the root of his disorder, Sahay and his colleagues proposed earlier this year.11 “We think neurogenesis affects the contextual processing, which then dictates the recruitment of stress and fear circuits.”
Of course, the big question is whether researchers might one day be able to harness neurogenesis in a therapeutic capacity. Some scientists, such as Hongjun Song of Johns Hopkins School of Medicine, say yes. “I think the field is moving toward [that],” he says. “[Neurogenesis] is not something de novo that we don’t have at all—that [would be] much harder. Here, we know it happens; we just need to enhance it.”
Three mechanisms of neurogenesis are discussed above: Two types of artificially induced neurogenesis — which should prove useful for research and regeneration. And natural adult neurogenesis which will eventually prove useful for in situ regeneration of some brain function.
Range of Stem Cell Types
Advances in stem cell research combined with powerful genetic technologies now allow unprecedented levels of investigation and manipulation of complex neuronal circuits. Previous efforts to implement cell-based therapies have been hindered by tumorigenesis, graft rejection, cell death, lack of circuit integration, and the inability to follow grafted cells in vivo. Scientific advances are beginning to tackle these challenges. Further, transsynaptic tracing has enabled high resolution dissection of neuronal circuits, which has begun to reveal insights into the molecular mechanisms that guide synapse formation and circuit integration in the living brain. Genetic approaches to manipulate neural circuit activity have allowed for the selective “activation” and “silencing” of discrete neuronal subtypes. This knowledge, combined with the ability to generate high numbers of neurons in vitro, promises to yield significant advances in cell therapy. In the future, it might be possible to manipulate injured and/or diseased brain circuits with artificially grafted cells, allowing for sustained symptomatic relief in a range of neurological disorder and neuronal injury models. __ http://journal.frontiersin.org/article/10.3389/fncel.2012.00059/full
Better tools for brain research will lead to better treatments for brain disease. Stem cells will eventually be used to re-grow damaged areas of the brain, and for in-situ regeneration of particular tissues within specific brain areas that are degenerating due to disease and ageing. We will look at more specifics involved in this area of research, as the field develops.
More brain research reading and news:
http://www.the-scientist.com/?articles.view/articleNo/44201/title/Epigenetic-Marks-Tied-to-Homosexuality/ ……. A “cure” for homosexuality? Or a quick way to turn straights into gays?