Sex Differences in Circulating Progenitor Cells

Abstract

Background: Lower levels of circulating progenitor cells (PCs) reflect impaired endogenous regenerative capacity and are associated with aging, vascular disease, and poor outcomes. Whether biologic sex and sex hormones influence PC numbers remains a subject of controversy. We sought to determine sex differences in circulating PCs in both healthy persons and patients with coronary artery disease, and to determine their association with sex hormone levels.

Methods and results: In 642 participants (mean age 48 years, 69% women, 23% black) free from cardiovascular disease, we measured circulating PC counts as CD45^med+ mononuclear cells coexpressing CD34 and its subsets expressing CD133, chemokine (C-X-C motif) receptor 4, and vascular endothelial growth factor receptor 2 epitopes using flow cytometry. Testosterone and estradiol levels were measured. After adjustment for age, cardiovascular risk factors, and body mass, CD34⁺ (β=-23%, P<0.001), CD34⁺/CD133⁺ (β=-20%, P=0.001), CD34⁺/chemokine (C-X-C motif) receptor 4-positive (β=-24%, P<0.001), and CD34⁺/chemokine (C-X-C motif) receptor 4-positive/CD133⁺ (β=-21%, P=0.001) PC counts, but not vascular endothelial growth factor receptor 2-positive PC counts were lower in women compared with men. Estradiol levels positively correlated with hematopoietic, but not vascular endothelial growth factor receptor 2- positive PC counts in women (P<0.05). Testosterone levels and PC counts were not correlated in men. These findings were replicated in an independent cohort with prevalent coronary artery disease.

Conclusions: Women have lower circulating hematopoietic PC levels compared with men. Estrogen levels are modestly associated with PC levels in women. Since PCs are reflective of endogenous regenerative capacity, these findings may at least partly explain the rise in adverse cardiovascular events in women with aging and menopause.

Keywords: CD133; CD34; CXCR4; estrogen; progenitor cell; vascular endothelial growth factor receptor 2.

Figure 1

Flow cytometry analysis of blood progenitor cells. A, Forward scatter and side scatter gates following lyse‐no wash of blood and the addition of fluorescent counting beads (left upper corner in plot). B, Gating of CD34⁺, low side scatter cells from blood leukocytes shown in (A). C, Histograms of CD45 expression in the CD34⁺ low side scatter cells (red histogram) shown in (B) or the CD34^– cells (grey histogram). D, The pattern of coexpression of CD34 and CD45^dim on blood progenitors shown in (C). E, The coexpression of CD133 and chemokine (C‐X‐C motif) receptor 4 (CXCR4) on CD34⁺CD45^dim blood progenitors shown in (C). F, The coexpression of CD133 and vascular endothelial growth factor receptor 2 (VEGF2R) on CD34⁺CD45^dim blood progenitors shown in (C). FSC‐A indicates forward scatter area.

Figure 2

Sex differences in hematopoietic progenitor cells in healthy individuals. For all hematopoietic progenitor cell populations, men had higher numbers of cells after adjusting for age, race, and body mass index.

Figure 3

The effect of aging on differences between hematopoietic progenitor cells in healthy individuals. Men continue to have greater numbers of CD34⁺(A), CD34⁺/CD133⁺ (B), CD34⁺/chemokine (C‐X‐C motif) receptor 4 (CXCR4⁺) (C), and CD34⁺/CD133⁺/CXCR4⁺ (D) cells throughout their life course compared with women; however, these differences attenuate later in life.