Hematopoietic stem cells (HSC) in the bone marrow provide lifelong production of blood cells. The function, frequency and cell cycle activity of HSC are subject to mouse strain-dependent, genetically determined quantitative variation. The key question we would like to address in this application is what the organismal consequences are of genetic variation in HSC. We hypothesized, based on evolutionary theory, that organismal consequences of random genetic variation may become phenotypically relevant at the organismal level during the aging process, when selective pressure is lower than during reproductive age. This variation may therefore affect life span. Our preliminary data indicate strong genetic linkage between quantitative genetic variation among recombinant inbred mice in the HSC compartment, in thymic involution and in life span. Based on these findings, we want to test the hypotheses that one, genetic variation in HSC function plays a role in the genetic variation in aging and life span, and two, that HSC affect life span through their role in thymic involution. Our studies would the first to identify a mechanism for natural variation in life span in mammals, and may open ways to manipulate stem cells to prevent age-related pathology. Furthermore, they will offer insight into the mechanisms and consequences of thymic involution, a process that is widely regarded as detrimental to the aging process. To test these hypotheses, we will use two mouse models where the cycling rate and frequency of HSC is decreased compared to control mice. At least one of these mouse strains, Tgfb2 mice backcrossed onto a C57BL/6 background, also has decreased thymic involution. The other mouse strain, B6.D2-chr4 mice, is congenic for a life span locus on chr. 4.
The specific aims are:
Specific aim 1 : To analyze thymic involution in B6.D2-chr.4 congenic mice.
Specific aim 2 : To analyze life span and the effect of the thymus on life span in B6.D2-chr.4 congenic mice and in Tgfb2 mice.
|de Almeida, Mariana Justino; Luchsinger, Larry L; Corrigan, David J et al. (2017) Dye-Independent Methods Reveal Elevated Mitochondrial Mass in Hematopoietic Stem Cells. Cell Stem Cell 21:725-729.e4|
|Luchsinger, Larry L; de Almeida, Mariana Justino; Corrigan, David J et al. (2016) Mitofusin 2 maintains haematopoietic stem cells with extensive lymphoid potential. Nature 529:528-31|
|Snoeck, Hans-Willem (2015) Can Metabolic Mechanisms of Stem Cell Maintenance Explain Aging and the Immortal Germline? Cell Stem Cell 16:582-4|
|Yvan-Charvet, Laurent; Pagler, Tamara; Gautier, Emmanuel L et al. (2010) ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 328:1689-93|