The Sex of Stem Cells
By: Anna Podnos
In the last several decades, sex and gender have become widely recognized as important biological and social variables in human research, and many strategies for incorporating sex in research design have been developed. However, as discussed in our Summer 2011 edition (see “Sexism in Biomedical Research”), stratifying experiments by sex is much rarer in animal and cell-based research (1). Regenerative therapies, such as stem cell transplantation, are being developed based on animal and cellular models, and a fundamental component may be missing. Significant sex differences have recently been found in the regenerative properties of various stem cells. Stems cells have the unique ability to differentiate into specific cell types and self-renew, so they have the potential to treat organ failure, cancers, and degenerative diseases.
When patients’ own stem cells cannot be used therapeutically, they may require a cellular transplant from a donor. The success of transplantation depends on the type of donor stem cells, the characteristics of host cells, and their interactions with pathways associated with the illness2. Research using animal models has found that biological sex is an important variable in proliferation and differentiation rates of stem cells3. For example, animal studies of hematopoietic stem cell transplantation (the only stem cell therapy in standard medical practice (4)) have found that that the sex of both donor and recipient animals affect the transplantation outcome (4). In addition, there are significant differences in the activation of mesenchymal stem cells (MSC) depending on their biological sex (3). Researchers found that female stem cells produced more proliferation- and inflammation-promoting factors than male cells. Female muscle-derived stem cells (MDSC), which have the capacity for myocardial repair, were another type of stem cell found to have more regenerative capacity than male MDSC (5). These sex differences may be therapeutically relevant, but there are few studies directly comparing different cell types in disease models (6).
Given that sex differences exist in stem cells, it is necessary to examine the causes of the dissimilarities, which may arise on genetic, epigenetic or hormonal levels. Male and female cells differ genetically, and it is important to investigate the differences both between and within sexes. The hormonal environment is a key covariate to sex, because it may also regulate the differentiation and proliferation of stem cells. Epigenetic differences resulting in varying gene expression levels are covariates as well. In mouse models of muscular dystrophy, it was found that not only do female MDSC promote more regeneration than male MDSC, but also that the female recipient animals undergo more regeneration than male animals do, regardless of the sex of the donor cells. However, this is not the case in immune-deficient animals, which suggests that the effect of host’s sex on the MDSC regenerative potential may be immunologically modulated, and therefore influenced by the hormonal environment.
It is challenging to appropriately incorporate sex as a variable in animal and cell-based study designs, so an interdisciplinary approach is often required. Recently, Stanford University launched “Gendered Innovations” (2) (genderedinnovations.stanford.edu), which has an abundance of information about the inclusion of sex and/or gender in engineering, science and medicine. It provides practical methods and checklists for considering biological sex in basic research. The development and implementation of specific guidelines for incorporating sex in stem cell research as an informative variable, rather than just a bias, will improve regenerative therapies.
- Beery, A., & Zucker, I. 2011. Sex Bias in Neuroscience and Biomedical Research. Neuroscience and Biobehavioral Reviews, 35 (3), 565-572
- Crisostomo, P., Markel, T., Wang, M., Lahm, T., Lillemoe, K., & Meldrum, D. 2007. In the Adult Mesenchymal Stem Cell Population, Source Gender Is a Biologically Relevant Aspect of Protective Power. Surgery, 142 (2), 215-221
- Gahrton, G., Iacobelli, S., Apperley, J., Bandini, G., Björkstrand, B., Bladé, J., Boiron, J., Cavo, M., Cornelissen, J., Corradini, P., Kröger, N., Ljungman, P., Michallet, M., Russell, N., Samson, D., Schattenberg, A., Sirohi, B., Verdonck, L., Volin, L., Zander, A., & Niederwieser, D. 2005. The Impact of Donor Gender on Outcome of Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma: Reduced Relapse Risk in Female to Male Transplants. Bone Marrow Transplantation, 35 (6), 609-617
- Deasy, B., Lu, A., Rubin, R., Huard, J., Tebbets, J., Feduska, J., Schugar, R., Pollett, J., Sun, B., Urish, K., Gharaibeh, B., & Coo, B. 2007. A Role for Cell Sex in Stem Cell-Mediated Skeletal Muscle Regeneration: Female Cells Have Higher Muscle Regeneration Efficiency. The Journal of Cell Biology, 177 (1), 73-86
- Zenovich, A., Davis, B., & Taylor, D. 2007. Comparison of Intracardiac Cell Transplantation: Autologous Skeletal Myoblasts versus Bone Marrow Cells. In Kauser, K., & Zeiher, A. (Eds.), Bone Marrow-Derived Progenitors, pp. 117-165. Berlin: Springer Verlag