|
|
Developmental Biology - Cell Aging
Reversing Aging In The Brains of Rats
Brains stiffen as we age and interrupt brain stem cell function...
New research, published in Nature, reveals that increasing brain stiffness with aging can be traced in dysfunctional brain stem cell activity — but, may be able to be reversed.
These research results have far reaching implications for how we understand our ageing process, and how we might develop much-needed treatments for age-related brain diseases.
As our bodies age, muscles and joints can become stiff, making everyday movements more difficult. This study shows the same is true in our brains, and that age-related brain stiffening has a significant impact on brain stem cell function.
A multi-disciplinary research team, based at the Wellcome-MRC Cambridge Stem Cell Institute (University of Cambridge, United Kingdom), studied young and old rat brains to understand the impact of age-related brain stiffening on the function of Oligodendrocyte Progenitor Cells (OPCs).
OPC cells are a type of brain stem cell important in maintaining normal brain function and in regenerating myelin - the fatty sheath that surrounds our nerves. They also can become severely damaged in Multiple Sclerosis (MS). The effects of age on OP cells contributes to MS, but their function also declines with age in healthy people.
To determine whether loss of function in aged OPCs was reversible, researchers transplanted older OPCs from aged rats into the soft, spongy brains of younger rats. Remarkably, the older rat brain cells were rejuvenated, and began behaving like younger, more vigorous cells.
To study this further, the researchers developed new materials in the lab with varying degrees of stiffness. Brain stem cells were then grown on these stiff materials in a controlled environment. The materials were engineered to have texture similar to both young or old brains.
To fully understand how brain softness and stiffness influences cell behavior, researchers investigated Piezo1 - a protein on the cell surface that informs the cell whether its surrounding environment is soft or stiff.
"We were fascinated to see that when we grew young, functioning rat brain stem cells on stiff material, the cells became dysfunctional and lost their ability to regenerate, and in fact began to function like aged cells. What was especially interesting, however, was that when old brain cells were grown on soft material, they began to function like young cells - in other words, they were rejuvenated."
Kevin J. Chalut PhD, Wellcome Trust-Medical Research Council, Cambridge Stem Cell Institute; Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge, UK and co-leader of the research.
"When we removed Piezo1 from the surface of aged brain stem cells, we were able to trick those cells into perceiving it as a soft surrounding environment, even when OPCs were growing on stiff material.
What's more, we were able to delete Piezo1 in OPCs within aged rat brains, which leads OPC cells to become rejuvenated and once again assume their normal regenerative function."
Robin J. M. Franklin PhD,
Wellcome Trust-Medical Research Council, Cambridge Stem Cell Institute; Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; and co-leader of the research with Dr Chalut.
Dr Susan Kohlhaas, Director of Research at the MS Society which partly funded the research, adds: "MS is relentless, painful, and disabling, and treatments that can slow and prevent the accumulation of disability over time are desperately needed. The Cambridge team's discoveries on how brain stem cells age and how this process might be reversed have important implications for future treatment. It gives us a new target to address issues associated with aging and MS, including how to potentially regain lost function in the brain."
Abstract
Ageing causes a decline in tissue regeneration owing to a loss of function of adult stem cell and progenitor cell populations (1). One example is the deterioration of the regenerative capacity of the widespread and abundant population of central nervous system (CNS) multipotent stem cells known as oligodendrocyte progenitor cells (OPCs) (2). A relatively overlooked potential source of this loss of function is the stem cell ‘niche’—a set of cell-extrinsic cues that include chemical and mechanical signals (3,4). Here we show that the OPC microenvironment stiffens with age, and that this mechanical change is sufficient to cause age-related loss of function of OPCs. Using biological and synthetic scaffolds to mimic the stiffness of young brains, we find that isolated aged OPCs cultured on these scaffolds are molecularly and functionally rejuvenated. When we disrupt mechanical signalling, the proliferation and differentiation rates of OPCs are increased. We identify the mechanoresponsive ion channel PIEZO1 as a key mediator of OPC mechanical signalling. Inhibiting PIEZO1 overrides mechanical signals in vivo and allows OPCs to maintain activity in the ageing CNS. We also show that PIEZO1 is important in regulating cell number during CNS development. Thus we show that tissue stiffness is a crucial regulator of ageing in OPCs, and provide insights into how the function of adult stem and progenitor cells changes with age. Our findings could be important not only for the development of regenerative therapies, but also for understanding the ageing process itself.
Authors
Michael Segel, Björn Neumann, Myfanwy F. E. Hill, Isabell P. Weber, Carlo Viscomi, Chao Zhao, Adam Young, Chibeza C. Agley, Amelia J. Thompson, Ginez A. Gonzalez, Amar Sharma, Staffan Holmqvist, David H. Rowitch, Kristian Franze, Robin J. M. Franklin & Kevin J. Chalut.
Acknowledgments
The authors thank D. Morrison for technical assistance and E. Paluch for helpful discussions and help with the manuscript. The work was supported by European Research Council (ERC) grant 772798 (to K.J.C.) and 772426 (to K.F.); the UK Multiple Sclerosis Society (to R.J.M.F.); Biotechnology and Biological Sciences Research Council (BBSRC) grant BB/M008827/1 (to K.J.C and R.J.M.F.) and BB/N006402/1 (to K.F.); the Adelson Medical Research Foundation (R.J.M.F. and D.H.R.); an EMBO Long-Term Fellowship ALTF 1263-2015 and European Commission FP7 actions LTFCOFUND2013, GA-2013-609409 (to I.P.W.); a Royal Society University Research Fellowship (to K.J.C.); and a core support grant from the Wellcome Trust and Medical Research Council (MRC) to the Wellcome Trust–MRC Cambridge Stem Cell Institute.
Return to top of page.
| |
|
Nov 6 2019 Fetal Timeline Maternal Timeline News
A Piezo Channel is a mechanosensitive ion channel (MscL) which converts an external mechanical stimuli into an electrochemical signal that conveys a sense of touch, balance, and even affects cardiovascular (blood flow) regulation. The mouse Piezo1 channel [ABOVE] has an array of arms surrounding its central pore. Click HERE to manipulate this Piezo Channel. CREDIT Guo YR, MacKinnon R. National Center for Biotechnology Information
|
Commons License.