Commercial human pulmonary artery endothelial cells have in‐vitro behavior that varies by sex

Abstract

It is unknown whether biological sex influences phenotypes of commercially available human pulmonary artery endothelial cells (HPAECs). Ten lots of commercial HPAECs were used (Lonza Biologics; PromoCell). Five (50%) were confirmed to be genotypically male ( SRY +) and five (50%) were confirmed to be female ( SRY −). Experiments were conducted between passages five and eight. HPAEC phenotype was confirmed with a panel of cell expression markers. Standard assays for proliferation, migration and tube formation were performed in triplicate with technical replicates, under three treatment conditions (EndoGRO; Sigma‐Aldrich). Apoptosis was assessed by exposing cells treated with complete media or low serum media to hypoxic (1% oxygen) or normoxic (20% oxygen) conditions. Laboratory staff was blinded. The median (range) age of male and female donors from whom the HPAECs were derived was 58 (48–60) and 56 (33–67), respectively. Our results suggest decreased proliferation in genotypically female cells compared with male cells ( p = 0.09). With increasing donor age, female cells were less proliferative and male cells were more proliferative ( p = 0.001). Female cells were significantly more apoptotic than male cells by condition ( p = 0.001). Female cells were significantly more migratory than male cells in complete media but less migratory than male cells under vascular endothelial growth factor enriched conditions ( p = 0.001). There are subtle sex‐based differences in the behavior of HPAECs that depend on donor sex and, less so, age. These differences may undermine rigor and reproducibility. Future studies should define whether biological sex is an important regulator of HPAEC function in health and disease.

Treating sex and gender differences as a continuous variable can improve precision cancer treatments

“…These data indicate that varying degrees of sex and gender - correlated gene expression exist across cancer types and that a predominant shared pattern between multiple cancers involves skewed gene expression in cell cycle regulation versus inflammation/immunity pathways. This validates the TI approach as these pathways are known to be strongly sex and gender-biased in action [ 11 – 14 ]. The replication of these polarization patterns across cancer types provides a measure of cross-validation for the approach.…”

“…An accompanying analysis of survival data from 3.7 million cases in the Surveillance, Epidemiology, and End Results (SEER) database, representing approximately 28% of the cancer population, confirmed that mortality rates are higher for males compared to females [ 2 ]. These clinically important sex and gender differences are concordant with described sex differences in cell biology including response to genotoxic stress [ 3 , 4 ], DNA repair [ 5 , 6 ], mutational burden and oncogenic mechanisms [ 7 , 8 ], metabolism [ 9 , 10 ], and cell cycle regulation [ 11 – 13 ], as well as in systems biology including: immunity [ 14 ], metabolism [ 15 , 16 ], tissue repair [ 17 , 18 ], and longevity [ 19 , 20 ]. This suggests that therapies for all cancer patients may be advanced by a realistic translation of sex and gender differences into clinical practice.…”

Accounting for sex differences variability in the design of sex-adapted cancer treatments

“…An accompanying analysis of survival data from 3.7 million cases in the SEER database, representing approximately 28% of the cancer population, confirmed that mortality rates are higher for males compared to females [2]. These clinically important sex differences are concordant with described sex differences in cell biology including, response to genotoxic stress [3,4], DNA repair [5,6], mutational burden [7,8], metabolism [9,10], and cell cycle regulation [11][12][13], as well as in systems biology including: immunity [14], metabolism [15,16], tissue repair [17,18], and longevity [19,20]. This suggests that therapies for all cancer patients may be advanced by a realistic translation of sex differences into clinical practice.…”

“…The most common polarizations occur around male -cell cycle regulation and female -inflammation/immunity in both adult and pediatric cancers. This serves as validation for this approach as both mechanisms are already known to exhibit male-and female-biased action under normal conditions [11][12][13][14]. As both pathways are targetable with available therapeutics [27,28], it is interesting to consider how the TSI approach might inform stratification for treatment.…”

Accounting for sex differences as a continuous variable in cancer treatments

“…An accompanying analysis of survival data from 3.7 million cases in the Surveillance, Epidemiology, and End Results (SEER) database, representing approximately 28% of the cancer population, confirmed that mortality rates are higher for males compared to females [2]. These clinically important sex differences are concordant with described sex differences in cell biology including response to genotoxic stress [3,4], DNA repair [5,6], mutational burden and oncogenic mechanisms [7,8], metabolism [9,10], and cell cycle regulation [11][12][13], as well as in systems biology including: immunity [14], metabolism [15,16], tissue repair [17,18], and longevity [19,20]. This suggests that therapies for all cancer patients may be advanced by a realistic translation of sex differences into clinical practice.…”