Research using sex as a variable has revealed sex differences in the properties of some adult stem cells. Findings include:
These sex differences may be therapeutically relevant—but because many variables besides sex influence cell behavior, and because the traits of an “ideal” cell type differ depending on the therapy in question, such differences do not indicate that cells of a given sex are broadly therapeutically superior to cells of the other sex. In clinical research using stem cells, there is a “lack [of] direct comparisons of different cell types in clearly defined, clinically relevant models of disease” (Zenovich et al., 2007).
Knowing that sex differences exist in stem cells, researchers sought to elucidate the causes of these differences—work that required analysis of additional factors (see Method).
Multivariate studies include sex as one variable among many. It is important to test for interactions between sex and other predictors of the outcome under study. Without such testing, one might attribute variability to sex when that difference is actually dependent on another factor. This misattribution can lead to
. Covariate analysis has shown the following:
When a patient’s own stem cells cannot be used therapeutically, success in stem cell transplantation depends on analyzing the interactions between: 1) the sex of donor cells used; 2) the sex of the host; 3) the type of stem cells transplanted; and 4) the illness being treated (see Method).
A study of 1,386 patients undergoing allogeneic HSC transplantation at a single medical center (about 75% for leukemias and the remainder for other conditions) showed that sex matching between donors and recipients correlated with better overall survival, although HSCs from male donors were associated with better long-term survival (Pond et al., 2006).
In pediatric leukemia, HSC transplantation from a female donor to a male recipient produces outcomes that are “unfavorable comparing with all other sex combinations” and “dismal in the presence of an MM (Human Leukocyte Antigen Mismatch).” Donor pregnancy was also found to interact with donor sex and recipient sex; when stem cells are derived from pregnant women donors and given to male patients, the risk of graft-versus-host disease increases (Gustaffson et al., 2004).
Systems for matching patients to donors for allogeneic HSC transplants now take donor sex and patient sex into account, along with numerous other variables, in order to optimize outcomes (Lee et al., 2007).
Researchers who reported and analyzed sex at the cellular level have identified sex differences in cell behavior that may be of relevance in developing therapeutics. These findings led researchers to investigate the causes of sex differences and discover both hormonal and genetic factors that govern stem cell behavior. In hematopoietic stem cell transplantation—the only stem cell therapy in widespread clinical use—clinicians have gathered data about interactions between donor sex, recipient sex, and other covariates in order to optimize donor-patient matching for allografts.
In basic research, scientists should be aware of the importance of sex as a variable and, in turn, identify the karyotype of cells used when reporting their research results. Results and null results should be reported (see Analyzing Sex). Reporting cell karyotype is important whether or not sex-based differences exist because this information permits secondary research reviews and meta-analyses. Granting agencies and journal editors can encourage such reporting through grant and publication guidelines.
Asselin-Labat, M., Vaillant, F., Sheridan, J., Pal, B., Simpson, E., Yasuda, H., Smyth, G., Martin, T., Lindeman, G., & Visvader, J. (2010). Control of Mammary Stem Cell Function by Steroid Hormone Signaling. Nature, 465 (7299), 798-802.
Beery, A., & Zucker, I. (2011). Sex Bias in Neuroscience and Biomedical Research. Neuroscience and Biobehavioral Reviews, 35 (3), 565-572.
Cowan, C., Klimanskaya, I., McMahon, J., Atienza, J., Witmyer, J., Zucker, J., Wang, S., Morton, C., McMahon, A., Powers, D., & Melton, D. (2004). Derivation of Embryonic Stem-Cell Lines from Human Blastocysts. New England Journal of Medicine, 350 (13), 1353-1356.
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.
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.
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.
Gratwohl, A., Baldomero, H., Aljurm, M., Pasquini, M., Bouzas, L., Yoshimi, A., Szer, J., Lipton, J., Schwendener, A., Gratwohl, M., Frauendorfer, K., Niederwieser, D., Horowitz, M., & Kodera, Y. (2010). Hematopoietic Stem Cell Transplantation: A Global Perspective. Journal of the American Medical Association, 303 (16), 1617-1624.
Gustaffson, Å., Remberger, M., Ringdén, O., & Winiarski, J. (2004). Risk Factors in Pediatric Stem Cell Transplantation for Leukemia. Pediatric Transplantation, 8 (5), 464-474.
Jankowski, R., Deasy, B., & Huard, J. (2002). Muscle-Derived Stem Cells. Gene Therapy, 9 (10), 642-647.
Lee, S., Klein, J., Haagenson, M., Baxter-Lowe, L., Confer, D., Eapen, M., Fernandez-Vina, M., Flomenberg, N., Horowitz, M., Hurley, C., Noreen, H., Oudshoorn, M., Petersdorm, E., Setterholm, M., Spellman, S., Weisdorf, D., Williams, T., & Anasetti, C. (2007). High-Resolution Donor-Recipient HLA (Human Leukocyte Antigen) Matching Contributes to the Success of Unrelated Donor Marrow Transplantation. Blood, 110 (13), 4576-4583.
Ohm, J., & Baylin, S. (2009). Stem Cell Epigenetics. In Rajasekhar, V., & Vemuri, M. (Eds.), Regulatory Networks in Stem Cells, Volume III: Stem Cell Biology and Regenerative Medicine, pp. 235-246. Berlin: Springer Science and Business Media.
Oreffo, R., Cooper, C., Mason, C., & Clements, M. (2005). Mesenchymal Stem Cells: Lineage, Plasticity, and Skeletal Therapeutic Potential. Stem Cell Reviews, 1 (2), 169-178.
Osafune, K., Caron, L., Borowiak, M., Martinez, R., Fitz-Gerals, C., Sato, Y., Cowan, C., Chien, K., & Melton, D. (2008). Marked Differences in Differentiation Propensity among Human Embryonic Stem Cell Lines. Nature Biotechnology, 26 (3), 313-315.
Pond, G., Lipton, J., & Messner, H. (2006). Long-Term Survival after Blood and Marrow Transplantation: Comparison with an Age- and Gender-Matched Normative Population. Biology of Blood and Marrow Transplantation, 12 (4), 422-429.
Ray, R., Novotny, N., Crisostomo, P., Lahm, T., Abaranell, A., & Meldrum, D. (2008). Sex Steroids and Stem Cell Function. Molecular Medicine, 14 (7), 493-501.
Tchieu, J., Kuoy, E., Chin, M., Trinh, H., Patterson, M., Sherman, S., Amiuwu, O., Lindgren, A., Hakimian, S., Zack, J., Clark, A., Pyle, A., Lowry, W., & Plath, K. (2010). Female Human Induced Pluripotent Stem Cells (iPSCs) Retain an Inactive X Chromosome. Cell, 7 (3), 329-342.
Zeller, C., Wang, Y., Markel, T., Weil, B., Abarbanell, A., Herrmann, J., Kelly, M., Coffey, A., & Meldrum, D. (2009). Role of Tumor Necrosis Factor Receptor 1 in Sex Differences of Stem-Cell-Mediated Cardioprotection. Annals of Thoracic Surgery, 87 (3), 812-819.
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.