The positive side of aging⎯stem cells to the rescue

The positive side of aging⎯stem cells to the rescue

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Authors: Cindi Morshead, PhD and Nadia Sachewsky, PhD

Affiliation: Professor and Chair, Division of Anatomy, Department of Surgery, University of Toronto, IMS Member; Post-doctoral Fellow, University of Toronto

Life expectancy has increased by >25 years in the last century (http://www.statcan.gc.ca) and the average Canadian now lives to an average age of 81.7 years. It is estimated that nearly half of this increase is the result of reduced infant mortality rates in the 1920-1950’s and the increases since that time are due to reduced deaths from circulatory diseases. This extended life span comes with a host of new challenges including disease and disability, which ultimately pose challenges for the health care system. For instance, there has been an increase in the prevalence of disease in the elderly including chronic diseases such as heart disease, arthritis, diabetes, and cancer. These findings highlight the need to focus our research attention on these diseases, but, equally important, the need to understand the biology of the aging population and the implications for developing therapeutic interventions to treat the elderly.

Stem cell biology is at the forefront in the field of regenerative medicine. Stem cells are found throughout development and into adulthood and can be isolated from a variety of tissues including heart, blood, muscle, and brain, to name a few. By definition, stem cells possess the ability to self-renew and make copies of themselves, as well as give rise to cells that will differentiate into mature cell types, which are confined to the tissue of origin. A number of stem cell populations are being explored for their therapeutic potential including embryonic stem cells, induced pluripotent stem cells, and adult tissue specific stem cells. Each of these cell types has benefits and drawbacks ranging from ethical concerns surrounding the source of the cells, issues of derivation, purification, and importantly, how they integrate within the host tissue. Stem cell based regenerative medicine strategies use two main approaches: (1) Exogenous therapy involving cell isolation, expansion, and transplantation in the injured or diseased organ, and (2) endogenous strategies that aim to activate and recruit stem cells in their existing niche in order to get them to contribute to “self-repair” of the injured or diseased organ. The Morshead lab focuses on endogenous repair strategies. With the goal of manipulating the resident cells within the patient using novel therapeutics or biologics, we propose that the activated resident cells will provide trophic support and/or replace lost cells. Importantly, endogenous recruitment sidesteps issues of immune rejection, cell transformation by culturing, surgical complications from transplants, and ethical concerns surrounding the source of cells. The benefits of this approach make it a promising and exciting area of research.

The Morshead lab focuses on repair of the central nervous system. The brain and spinal cord contain populations of neural stem cells that were originally identified by Reynolds and Weiss over two decades ago.1,2 In the brain, these rare cells and their progeny are found lining the fluid-filled ventricles in a region termed the subependyma. Neural stem cells are found through development and into old age, and in the murine brain they are responsible for ongoing olfactory bulb neurogenesis throughout the lifetime of the animal. These resident stem cells are the target for brain repair strategies and indeed, they have the properties that would make them good candidates to promote repair; they are found throughout the lifetime of the animal, they are proliferative, and give rise to progeny that can differentiate into all neural cell types that comprise the central nervous system tissue (neurons, astrocytes and oligodendrocytes). The goal is to harness their potential to repair the diseased or injured brain.

What is abundantly clear is that despite their presence in the brain, injury alone is not sufficient to activate these cells and promote brain repair. Most interestingly, while brain injury alone is sufficient to increase the numbers of neural stem cells and their progeny in the young adult brain, this activation does not result in tissue repair or recovery of lost function. However, we, and others, have achieved success using biologics such as drugs, growth factors and small molecules, to facilitate the activation of endogenous precursors following injury.3-5 Indeed, in a number of proof of principle studies, we demonstrated that administration of biologics following stroke can lead to enhanced neural stem and progenitor activation, tissue repair, and recovery of lost function following injury.   Importantly, these studies were performed in models of stroke in the young adult brain. Stroke is the third leading cause of death in Canada (second in the world) with 50 000 deaths annually and thousands left with permanent motor and cognitive impairments.   Hence, while the findings were promising and suggested hope for using stem cell based strategies to promote self-repair, the question remains as to whether these strategies will be equally effective across different ages that can suffer stroke. While stroke can affect humans at any age, occurrence in the aged population is particularly high where the risk of stroke doubles every 10 years over the age of 55 (Heart and Stroke Foundation).

What we know is that the brain changes with age. Hence, the fact that a therapeutic intervention shows promise in young adult brains does not necessarily translate into success in the aged brain. This underlies the importance of understanding the fundamental biology of neural stem cells in the aged brain⎯their numbers, proliferation kinetics, their responsiveness to injury and biologics⎯in particular as it relates to those interventions that demonstrate success in the young brain. Our lab and others have shown that with age, neural stem cells and their progeny are less active in general, and are less responsive to injury.6-7 For instance, neural stem cells and their progeny are less proliferative and generate few new neurons in the aged brain, but if you transplant these aged stem cells into a younger brain, they behave as though they were young.7 Clearly something is different about the environment in the aged brain. The differences are further demonstrated following injury. In a young brain, stroke injury alone is able to activate the endogenous stem and progenitor cells; however, this activation does not occur in the aged brain.7 This change in responsiveness to environmental cues (i.e. injury) is an important consideration when designing stem cell based interventions to treat the aged.

The Morshead lab has taken this challenge to heart and has specifically set out determine whether our brain repair strategies are effective in aged cohorts of animals. A layer of complexity is added to these studies as it is expensive to age animals, which must be housed for well over a year before they can be used in the studies. Further, the health of the animals is compromised with age and this can add to the expense and time required to perform the experiments. Despite these potential roadblocks, Nadia Sachewsky (an IMS graduate and current Postdoctoral Fellow in the Morshead group), took on the challenge. We had established that Cyclosporin A (CsA), an FDA drug used typically to prevent graft rejection following transplantation, can enhance neural stem cell survival5,8 and elicit tissue repair and functional recovery in young adult animals following stroke injury.4,5 Moreover it was effective in two distinct models of stroke and in more than one strain of mice. Would CsA be effective in old age stroke lesioned mice? Interestingly, initial experiments were not promising, as CsA did not promote survival of aged neural stem cells even in a simple culture assay. In light of the fact that injury alone did not activate aged endogenous neural stem cells, and CsA did not seem to promote their survival, we were less optimistic about seeing a positive outcome. However, what we found was that the combination of CsA and stroke injury in aged animals resulted in significant activation (increased proliferation) of neural stem and progenitor cells, effectively increasing the size of the neural stem and progenitor pool. With this in hand, we performed stroke and CsA administration chronically for one month in old age mice and, identical to what we observed in young animals, aged mice displayed functional recovery. Hence, while aged neural stem cells are less responsive than their younger counterparts, their behavior can be modified to the same extent as young adult neural stem and progenitor cells.

These studies highlight the importance of understanding the basic biology of stem cell populations in the brain and the need to remain mindful of the fact that the population is aging. It also speaks to the promise of endogenous repair strategies as a means to promote regenerative medicine. One cannot underestimate the importance of developing successful therapeutic interventions that are applicable to our aging population as these will ultimately have profound impact on our quality of life.

References:

  1. Reynolds BA, Weiss S. Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system. Science. 1992 Mar 27;255(5052):1707-1710.
  2. Reynolds BA, Weiss S. Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev Biol. 1996;175(1):1-13.
  3. Kolb B, Morshead C, Gonzalez C, et al. Growth factor-stimulated generation of new cortical tissue and functional recovery after stroke damage to the motor cortex of rats. J Cereb Blood Flow Metab. 2007;27(5):983-997.
  4. Erlandsson A, Lin CH, Yu F, et al. Immunosuppression promotes endogenous neural stem and progenitor cell migration and tissue regeneration after ischemic injury. Exp Neurol. 2011;230(1):48-57.
  5. Sachewsky N, Hunt J, Cooke MJ, et al. Cyclosporin A enhances neural precursor cell survival in mice through a calcineurin-independent pathway. Dis Model Mech. 2014;7(8):953-961.
  6. Enwere E, Shingo T, Gregg C, et al. Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J Neurosci. 2004;24(38):8354-8365.
  7. Piccin D, Tufford A, Morshead CM. Neural stem and progenitor cells in the aged subependyma are activated by the young niche. Neurobiol Aging. 2014;35(7):1669-1679.
  8. Hunt J, Cheng A, Hoyles A, et al. Cyclosporin A has direct effects on adult neural precursor cells. J Neurosci. 2010;30(8):2888-2896.