Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Pathology and Laboratory Medicine

Supervisor

Khan, Z.A.

2nd Supervisor

Howlett, C.

Affiliation

LHSC

Co-Supervisor

Co-Supervisor

Abstract

As we age, our bodies lose the ability to repair damaged tissues. This impairment may be due to age-related deficits in our regenerative stem cells. Stem cells reside in specialized areas called stem cell niches. Ageing may cause alterations in the stem cells directly or may alter the stem cell niche to generate deficits. However, systematic studies mapping stem cell deficits and alterations to stem cell niche are lacking. Here, I investigated the bone marrows of young and aged mice to determine age-related changes in the microenvironment that may alter resident stem cells.

To achieve my research objective, I examined the bone tissues of male and female C57BL/6N mice at different ages, ranging from 8 to 71 weeks of age. This corresponds to 20-75 human years. I performed bone marrow morphometric analyses and show an increase in marrow adiposity with advanced ageing in both male and female mice. I then stained bone tissues and noted increased immunoreactivity to stem cell antigen (SCA1) only at the middle age in female mice. This increase was not seen in male mice. Screening for various genes in the marrow flush samples indicated a possible role of growth and sex steroid hormone receptors in mediating some of the changes. However, empirical evidence will be needed to determine the causative agent in increased bone marrow adiposity.

My studies may allow for a better understanding of how ageing affects the composition and function of marrow resident stem cell populations.

Summary for Lay Audience

Ageing is a complex process which occurs in all organisms. As we age, our bodies lose the ability to repair tissue damage, which contributes to the occurrence of age-related diseases in elderly populations. Since stem cells are responsible for replenishing the aged and damaged cells, the decline of regenerative stem cells may contribute to our inability to repair tissues. Recent studies have indicated that stem cell fate is indirectly influenced by the composition of their cellular environment, the niche. Since the bone marrow houses different regenerative stem cell types and has a rich microenvironment that is known to change with ageing, it is an excellent model to investigate the mechanisms which may contribute to stem cell deficits with ageing. Therefore, I hypothesize that age-related cellular changes in the bone marrow are associated with the marrow resident stem cell ageing phenotype.

To understand how ageing negatively impacts regenerative stem cells, I examined the bone tissues of male and female mice at different ages. I harvested the bones from the limbs of mice at 8, 24, 48, 58-61, and 67-71 weeks of age. These timepoints correspond to approximately 20 to 75 human years. My results showed that the bone marrows of mice become fatty as they age. The detection of cellular and molecular changes associated with ageing suggest that the bone marrow microenvironment might regulate the stem cell ageing process.

Overall, my studies will allow for a better understanding of how ageing effects the composition and function of marrow resident stem cell populations. I anticipate that these studies will lead to the identification of targets for the prevention of ageing-related ailments.

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