Why Age-Specific Stem Cells Are Important
The Impact of Donor Stem Cell Age on Regenerative Potential, Differentiation and Immune Rejection
The age of donor stem cells is an important biological variable that impacts biochemical, physiological and clinical endpoints1. Aging tissues experience a progressive decline in homeostatic and regenerative capacities, which has been attributed to degenerative changes in tissue-specific stem cells, stem cell niches and systemic cues that regulate stem cell activity2. The age of tissues from which stem cells are derived is therefore an important variable that needs to be taken into consideration in basic research, and when developing regenerative biologic therapies.
Some of the well-established differences in properties of young- and old-derived stem cells are summarized below.
Stem Cell Proliferation and Regeneration: Aside from immunogenic issues, the proliferative and differentiative capabilities of stem cells are key to the success of cell therapies. In this context, inconsistent results have been reported, with some researchers demonstrating a decline in regenerative potential3, and others no change in regenerative potential4, with aging. It is unclear whether these differences are cell specific, or environment specific (e.g. age of animal). Nonetheless, the possibility that old stem cells have regenerative potential is particularly important for autologous applications in the aging population.
Differentiation Potential: Aging has been shown to impact differentiation in a number of cell types. For example, aged hematopoietic stem cells (HSCs) are more likely to differentiate towards the myeloid lineage at the expense of the lymphoid lineage5-7. Furthermore, like HSCs, aged satellite cells (muscle stem cells) exhibit a skewed differentiation potential, whereby they differentiate towards a fibrogenic lineage rather than a myogenic lineage, largely because of changes in Wnt and TGF-β signaling8-11. Aging may also shift mesenchymal stem cells (MSC) lineage differentiation from one that usually favors osteoblastic differentiation to one that prefers adipogenic differentiation12.
Clinical Evidence: Next to HLA matching, the age of a stem cell donor is the most important characteristic influencing leukemia patient survival following a hematopoietic cell transplantation. A linear relationship between age of donor and patient survival has been identified, with younger donors associated with better survival rates for patients13. A 10-year younger donor offers a 3% increase in patient survival two years after transplant, regardless of other donor characteristics. Blood stem cells from older donors are more prone to inflammation, produce more myeloid cells and fewer lymphocytes – and are more likely to be affected by clonal hematopoiesis, a mutation of blood cells that can increase the risk of blood cancer and overall mortality. Moreover, there is some evidence that Graft versus Host Disease – where donor cells attack the patient’s organs – is more likely where a patient has an older donor, and may be explained by naïve T cells being replaced with memory T cells as the immune system ages 14. Age of stem cells is therefore an important variable that allows transplant clinicians to be more confident when selecting a donor for a patient with multiple matching donors. These findings have important implications for stem cell transplantation for regenerative purposes.
DNA damage and telomere shortening
In one of the world’s oldest women, 450 somatic mutations were found across 115 years of her life. This equates to four mutations per year or about three mutations per division given HSCs renew every 25 to 50 weeks15. It is not known if mutation rate increases with age. Although stem cells express telomerase, the telomeres of HSCs, MSCs, NSCs, HFSCs and GSCs do shorten with age16-18. The impact of telomere shortening on the regenerative potential of stem cells is unclear19, 20.
Studies have suggested a direct relationship between mitochondrial dysfunction and human stem cell aging21-24. It is also evident that with increasing donor age, MSCs from both bone marrow and adipose tissues have reduced capacity to handle oxidative stress25, 26.
Epigenetic marks in stem cells are transmitted heritably to their daughter cells, priming lineage-specific loci for modification in downstream progenies27. Stem cell fates are regulated by epigenetic modifications of DNA that establish the memory of active and silent gene states28, 29. Aberrant epigenetic regulation affects age-associated dysfunction of stem cells, and predisposition to hematological cancers development30. For instance, DNA methylation specific to regions of the genome that are important for lineage-specific gene expression increased in aging HSCs31 and the perturbations of their histone modifications (H3K4me3) may impair its self-renewal genes32. MicroRNAs (miRNAs) are another key class of epigenetic mediators of stem cell dysfunction and they are differentially expressed during aging33. They co-regulate stem cell properties such as potency, differentiation, self-renewal and senescence34. For instance, the MiR-290–295 cluster seems to promote embryonic stem cell differentiation, self-renewal, and maintenance of pluripotency35, 36.
Source of Stem Cells: Stem cells from cord blood are among the youngest retrievable adult stem cells. Cord blood stem cells have not been exposed to factors that inhibit proper function as with older stem cells from other sources. This makes cord blood a better source when HLA-matching is equal.
JangoBio has generated an array of stem cells from animals of different ages for experimental research. Moreover, the effects of aging on regenerative medicine therapies may be different in men and women. Reach out to JangoBio for your age-, gender- and tissue-specific stem cell needs!
- Ahmed AS, Sheng MH, Wasnik S, et al. Effect of aging on stem cells. World J Exp Med. 2017;7(1):1-10.
- Oh J, Lee YD, Wagers AJ. Stem cell aging: mechanisms, regulators and therapeutic opportunities. Nat Med. 2014;20(8):870-880.
- Williams JK, Dean A, Lankford S, et al. Determinates of muscle precursor cell therapy efficacy in a nonhuman primate model of intrinsic urinary sphincter deficiency. Stem Cell Res Ther. 2017;8(1):1.
- Neal A, Boldrin L, Morgan JE. The satellite cell in male and female, developing and adult mouse muscle: distinct stem cells for growth and regeneration. PLoS One. 2012;7(5):e37950.
- Sudo K, Ema H, Morita Y, et al. Age-associated characteristics of murine hematopoietic stem cells. J Exp Med. 2000;192(9):1273-1280.
- Liang Y, Van Zant G, Szilvassy SJ. Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood. 2005;106(4):1479-1487.
- Rossi DJ, Bryder D, Zahn JM, et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A. 2005;102(26):9194-9199.
- Brack AS, Rando TA. Intrinsic changes and extrinsic influences of myogenic stem cell function during aging. Stem Cell Rev. 2007;3(3):226-237.
- Brack AS, Conboy MJ, Roy S, et al. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science. 2007;317(5839):807-810.
- Carlson ME, Suetta C, Conboy MJ, et al. Molecular aging and rejuvenation of human muscle stem cells. EMBO Mol Med. 2009;1(8-9):381-391.
- Carlson ME, Conboy MJ, Hsu M, et al. Relative roles of TGF-beta1 and Wnt in the systemic regulation and aging of satellite cell responses. Aging Cell. 2009;8(6):676-689.
- Liu H, Xia X, Li B. Mesenchymal stem cell aging: Mechanisms and influences on skeletal and non-skeletal tissues. Exp Biol Med (Maywood). 2015;240(8):1099-1106.
- Shaw BE, Logan BR, Spellman SR, et al. Development of an Unrelated Donor Selection Score Predictive of Survival after HCT: Donor Age Matters Most. Biol Blood Marrow Transplant. 2018;24(5):1049-1056.
- Becklund BR, Purton JF, Ramsey C, et al. The aged lymphoid tissue environment fails to support naive T cell homeostasis. Sci Rep. 2016;6:30842.
- Holstege H, Pfeiffer W, Sie D, et al. Somatic mutations found in the healthy blood compartment of a 115-yr-old woman demonstrate oligoclonal hematopoiesis. Genome Res. 2014;24(5):733-742.
- Bonab MM, Alimoghaddam K, Talebian F, et al. Aging of mesenchymal stem cell in vitro. BMC Cell Biol. 2006;7:14.
- Ferron SR, Marques-Torrejon MA, Mira H, et al. Telomere shortening in neural stem cells disrupts neuronal differentiation and neuritogenesis. J Neurosci. 2009;29(46):14394-14407.
- Flores I, Canela A, Vera E, et al. The longest telomeres: a general signature of adult stem cell compartments. Genes Dev. 2008;22(5):654-667.
- Ju Z, Lenhard Rudolph K. Telomere dysfunction and stem cell ageing. Biochimie. 2008;90(1):24-32.
- Lee HW, Blasco MA, Gottlieb GJ, et al. Essential role of mouse telomerase in highly proliferative organs. Nature. 1998;392(6676):569-574.
- Bratic A, Larsson NG. The role of mitochondria in aging. J Clin Invest. 2013;123(3):951-957.
- Taylor RW, Barron MJ, Borthwick GM, et al. Mitochondrial DNA mutations in human colonic crypt stem cells. J Clin Invest. 2003;112(9):1351-1360.
- McDonald SA, Greaves LC, Gutierrez-Gonzalez L, et al. Mechanisms of field cancerization in the human stomach: the expansion and spread of mutated gastric stem cells. Gastroenterology. 2008;134(2):500-510.
- Fellous TG, McDonald SA, Burkert J, et al. A methodological approach to tracing cell lineage in human epithelial tissues. Stem Cells. 2009;27(6):1410-1420.
- Sethe S, Scutt A, Stolzing A. Aging of mesenchymal stem cells. Ageing Res Rev. 2006;5(1):91-116.
- Stolzing A, Jones E, McGonagle D, et al. Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech Ageing Dev. 2008;129(3):163-173.
- Beerman I, Rossi DJ. Epigenetic Control of Stem Cell Potential during Homeostasis, Aging, and Disease. Cell Stem Cell. 2015;16(6):613-625.
- Borrelli E, Nestler EJ, Allis CD, et al. Decoding the epigenetic language of neuronal plasticity. Neuron. 2008;60(6):961-974.
- Orkin SH, Hochedlinger K. Chromatin connections to pluripotency and cellular reprogramming. Cell. 2011;145(6):835-850.
- Buscarlet M, Tessier A, Provost S, et al. Human blood cell levels of 5-hydroxymethylcytosine (5hmC) decline with age, partly related to acquired mutations in TET2. Exp Hematol. 2016;44(11):1072-1084.
- Beerman I, Bock C, Garrison BS, et al. Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging. Cell Stem Cell. 2013;12(4):413-425.
- Sun D, Luo M, Jeong M, et al. Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal. Cell Stem Cell. 2014;14(5):673-688.
- Smith-Vikos T, Slack FJ. MicroRNAs and their roles in aging. J Cell Sci. 2012;125(Pt 1):7-17.
- Hodzic M, Naaldijk Y, Stolzing A. Regulating aging in adult stem cells with microRNA. Z Gerontol Geriatr. 2013;46(7):629-634.
- Gangaraju VK, Lin H. MicroRNAs: key regulators of stem cells. Nat Rev Mol Cell Biol. 2009;10(2):116-125.
- Houbaviy HB, Murray MF, Sharp PA. Embryonic stem cell-specific MicroRNAs. Dev Cell. 2003;5(2):351-358.