Reprogramming Astrocytes into Neurons Enhances Stroke Recovery in Mice
Reprogramming cells in order to change their cell type directly has shown some promise in animal studies as a way to generate new neurons in the brain, enabling regeneration. There are many more supporting cells in the brain, various types collectively known as glial cells, than there are neurons. These supporting cells are somewhat more fungible and replaceable, as they are not storing the data of the mind. A gene therapy that turns some small percentage of glial cells into neurons capable of integrating into existing neural circuits could prove to have numerous advantages over the cell therapy approach of growing patient-matched neurons and introducing them into the brain. Logistically, it should be considerable easier, for one. It may also turn out to be more effective, given the challenges inherent in keeping transplanted cells alive for any meaningful length of time following treatment.
Stem cell transplantation has emerged as a promising regenerative therapy for stroke due to its potential for repairing damaged brain structures and improving functional recovery. However, cell transplantation therapies face multiple obstacles including the hosts' immune systems, poor transplanted cell survival, inappropriate migration/homing and differentiation, and the lack of specificity or integration into endogenous brain networks. Some clinical trials have also reported inconsistent results in the efficacy of cell transplantation therapies.
Resident astrocytes in the brain remain mitotic throughout the lifespan and undergo rapid gliosis in response to injury. This characteristic response provides a rich source of cells adjacent to the site of injury. The idea of direct reprogramming of non-neuronal cells allows for the trans-differentiation of glial cells (astrocytes, microglia, and oligodendrocytes) into induced neurons (iNeurons) without passing through a stem cell stage. Theoretically, this is a more efficient way to obtain desirable endogenous neurons from a large cellular pool for "on-site" repair in the brain.
Based on the efficiency and efficacy of glial cell reprogramming, we and others experimented with several combinations of transcription factors and settled on the use of the single neural transcription factor NeuroD1 (ND1). Targeting astrocytes for neuronal reprogramming with different viral vectors has been tested in several animal models of neurodegenerative diseases including ischemic stroke with varying success. The exploration of this approach in animal disease models is at an early stage. The efficacy of neuronal conversion and its contribution to neuronal circuitry repair, the mechanisms involved in the regenerative process, and the functional benefits of this therapy have not been well defined.
Our investigation examined the viability of reprogramming of astrocytes in vitro and in vivo. Reprogramming therapy was tested in a focal ischemic stroke model of rats. After a stroke, we transduced ND1 using a lentivirus vector rather than other viral serotypes such as an adeno-associated virus (AAV) to preserve finer control over the scope of infection to study the mechanics of reprogramming on local circuitry and to limit the therapy to only the injured tissue. Neuronal network repair and functional recovery were confirmed using comprehensive assessments and behavioral tests up to 4 months after stroke. The present investigation presents compelling evidence for the feasibility and effectiveness of utilizing reactive astrocytes as an endogenous cellular source for the generation of neuronal cells to repair damaged brain structures.
While quite interesting I am a bit skeptical that this approach could work well in humans within next 3 decades. I guess, the lower hanging fruit is addressing the vasculative issues. No real need to understand the mind and the brain function, only keep the vessels in good shape.
p.s. I would be happy to be proven wrong.
@cuberat "the next 3 decades"? That's quite a long time. I sure hope we find some sort of breakthrough for aging within the next decade..
@Person1234
we already have "some" anti-aging treatments as proof of concept in mice. We could we some degree of certainty understand how all the tissues work and fix the failing ones. The brain might turn to be hard to understand and fixing it without altering the personality. This is why I am not holding my breath for this specific approach. From what we see , probably with senolytics , CR mimetics and a bit of cell/cellular vesicles replenishment we can get a lot of low hanging fruits. The other promising path is removing extra-cellular junk. Like lipofuscin and atherosclerosis plaques. Those are very likely to be available at least in human trials by 2030.
In the best , yet plausible, case scenario we could get finished human trials for some senolytic therapies by 2025 and a few years later the junk-clearing treatments.
Surprisingly enough, the worst case scenario would delay all of this by some 15-20 years. Enough to make a huge personal difference but minuscule in the big scheme of things. And probably, the biggest progress we have now is due to Aubrey advocating efforts to shift the mainstream perception.