Female-Derived Cell Models: Why Sex as a Biological Variable Matters in Research

Updated Aug 11, 2026.

For many years, female donor-derived cells were significantly underrepresented in preclinical research, limiting both our understanding of human biology and the development of effective treatments. As research policies increasingly emphasize the inclusion of female cell lines, researchers are gaining a clearer picture of why representation matters.

Today, sex as a biological variable (SABV) is increasingly recognized as an important factor that can influence gene expression, cell signaling, disease mechanisms, and responses to treatment. Incorporating female-derived cell models can help researchers determine whether a phenotype is consistent across sexes—or reveal biological differences that might otherwise be overlooked.

A Shift in Perspective: Recognizing Sex Differences in Research

Historically, the scientific community often operated under the assumption that male and female biology were sufficiently similar, allowing researchers to disregard sex as a variable in clinical research (Mauvais-Jarvis et al., 2020). This perspective was influenced by several factors, including the convenience of using male subjects, concerns about hormonal fluctuations in females introducing variability, and protective attitudes toward women of childbearing age.

For instance, researchers were wary that the estrous cycle in females could complicate experimental results due to hormonal changes, leading to inconsistent data. Additionally, ethical considerations about exposing women to potential risks during clinical trials, especially if they were pregnant or could become pregnant, further justified their exclusion.

However, over time, it became increasingly evident that biological differences between sexes extend beyond reproductive anatomy and hormonal cycles. Sex-specific variations influence numerous physiological processes, disease progression, and responses to treatment. The underrepresentation of women in research meant that biomedical advancements were not benefiting women and men equally, leading to gaps in knowledge and healthcare disparities.

To address this disparity, the National Institutes of Health (NIH) implemented the NIH Revitalization Act in 1993, mandating the inclusion of women in all NIH-funded clinical research. This policy aimed to ensure that clinical trials would provide data relevant to both sexes, improving the safety and efficacy of medical interventions for everyone. Despite this mandate, compliance was gradual, and the consequences of delayed implementation were significant. Between 1997 and 2000, the FDA withdrew eight out of ten drugs from the market due to greater health risks in women compared to men (GAO-01-286R, 2001). These incidents underscored the critical need for female representation in clinical research to identify sex-specific adverse effects and optimize therapeutic strategies.

Emphasizing Sex as a Biological Variable (SABV) in Preclinical Research

Women's participation in NIH-funded clinical trials increased from the beginning of the 21st century, reaching a point by the mid-2010s where approximately half of the study participants were women (Clayton and Collins, 2014). This shift marked significant progress toward gender parity in clinical research. However, this parity was not achieved in preclinical research, where studies often continued to overlook sex-specific differences despite clear evidence of such variations in experimental results obtained from primary cells and animal models (Du et al., 2004; Deasy et al., 2007; Nelson et al., 2007).

Preclinical studies form the foundation upon which clinical trials are built. Neglecting sex as a variable at this stage can lead to an incomplete understanding of disease mechanisms and potential treatments. Recognizing this gap, the NIH introduced the Sex as a Biological Variable (SABV) policy in 2016. SABV requires researchers seeking NIH funding to account for sex-based variability in their study designs. Researchers must provide a strong scientific justification for using single-sex models, supported by preliminary data or existing literature.

This policy ensures that considerations of sex differences are as rigorous as other critical aspects of study design, such as randomization and sample size calculation. By integrating SABV into research planning, scientists can produce more comprehensive and generalizable findings, ultimately improving the translation of preclinical research into effective clinical therapies for both men and women.

What Are Female-Derived Cell Models?

Female-derived cell models are cells obtained from female donors or organisms and used to study biological processes, disease mechanisms, genetic pathways, or therapeutic responses.

Depending on the research question, these models can include:

• Primary cells collected directly from a female donor
• Immortalized cell lines derived from female tissue
• iPS cells generated from female donor cells
• CRISPR-engineered cells carrying specific genetic modifications
• Differentiated iPS-derived cells used to model tissues or disease states

Each model offers different advantages. The most appropriate choice depends on the biological question, cell type, disease model, and experimental design.

The Impact of SABV on iPSC and CRISPR Technologies

The implementation of SABV coincided with revolutionary advancements in induced pluripotent stem cells (iPSCs) and CRISPR gene-editing technologies. iPSCs are reprogrammed somatic cells capable of differentiating into virtually any cell type, providing a versatile platform for biomedical research. The combination of iPSC technology with CRISPR gene editing has opened new avenues in several key areas:

1. Development of Precise Disease Models

Researchers can create patient-specific iPSC lines that carry genetic mutations associated with particular diseases. CRISPR enables precise editing of these genomes to introduce or correct mutations, facilitating the study of disease mechanisms at a cellular level.

2. Consistent Systems for Drug Screening and Toxicity Assessments

iPSC-derived cells offer a renewable source of human cells for high-throughput screening of drug candidates. Including cells from both sexes allows for assessing sex-specific drug responses, improving the prediction of efficacy and safety profiles.

3. Engineering of Cell-Based Therapies

iPSCs can be differentiated into cell types needed for regenerative medicine. CRISPR editing can enhance these cells by correcting genetic defects or adding beneficial traits, such as resistance to immune rejection.

SABV ensures that these powerful tools are used responsibly, promoting equitable benefits across sexes. By incorporating both male and female-derived iPSCs in research, scientists can uncover sex-specific differences in disease pathology and treatment responses, leading to more personalized and effective therapies.

Recognizing Sex Differences in Cell-Based Studies

Sex-specific variations are not limited to whole organisms; they are also evident at the cellular level, including in iPSCs and their derivatives. Studies have demonstrated differences in gene expression patterns between male and female undifferentiated iPSCs (Ronen & Benvenisty, 2014). These variations can influence cell behavior, differentiation potential, and response to stimuli.

Moreover, structural differences have been observed in tissues derived from iPSCs of different sexes (Weber & Clyne, 2021). For example, sex-specific variations in cardiac tissue architecture or neuronal connectivity could impact the accuracy of disease models and the development of treatments. Acknowledging these differences is crucial for accurate modeling and understanding of diseases, as it allows researchers to identify sex-specific mechanisms and tailor interventions accordingly.

Significance in Cardiovascular Research

Cardiovascular biology has been a focal point for studying sex-specific differences due to the contrasting incidence and outcomes of cardiovascular diseases between men and women. While men are generally at higher risk of developing cardiovascular diseases at a younger age, women often experience more severe outcomes and have a higher risk of drug-induced cardiac events (Gao et al., 2019). These disparities highlight the importance of understanding sex-specific cardiac physiology and pharmacology.

Studies using iPSC-derived cardiomyocytes have demonstrated significant differences between male and female cells. For instance, research has shown that female cardiomyocytes tend to have greater QT interval prolongation in response to certain drugs, a phenomenon largely independent of sex hormones (Huo et al., 2019). QT interval prolongation is associated with an increased risk of torsades de pointes, a life-threatening arrhythmia. This finding is critical for drug development, as it underscores the need to assess cardiac safety in both male and female models to prevent adverse effects that may disproportionately affect women.

By including female-derived cardiomyocytes in preclinical studies, researchers can identify sex-specific drug responses and adjust dosing or develop alternative therapies accordingly. This approach enhances the safety and efficacy of cardiovascular drugs for all patients.

Advancing Neurological Studies with Female-Derived Cells

Neurological diseases often exhibit sex-specific prevalence and manifestations, making the inclusion of female-derived cell models essential in neuroscience research. For example, schizophrenia has a higher incidence in males and often presents with more severe symptoms. Studies using iPSC-derived neurons have revealed sex-specific gene expression patterns that may contribute to these differences.

In a study examining schizophrenia using iPSC-derived neurons from disease-discordant monozygotic twins, researchers found that different sets of genes were differentially expressed between affected and unaffected individuals in a sex-specific manner (Tiihonen et al., 2019). These insights suggest that underlying disease mechanisms may vary between sexes, indicating a potential need for tailored treatments.

Similarly, neurodegenerative diseases like Alzheimer's disease show sex-specific trends, with women being more affected than men. Understanding how female-derived neurons respond to disease-associated proteins can inform the development of targeted therapies.

Including female-derived cell models in neurological studies enables researchers to explore how sex influences disease progression, neuronal function, and response to treatment. This knowledge is crucial for developing effective interventions that address the needs of both men and women.

Female Representation in CRISPR-Engineered Disease Models

The increased focus on sex-specific variability has led to greater demand for CRISPR-edited female iPSC lines in disease modeling. Access to female iPSC lines allows researchers to:

• Confirm That Study Results Are Consistent Across Sexes: Including both male and female models ensures that findings are universally applicable or helps identify sex-specific differences that may influence treatment outcomes.
• Model Conditions Specific to Females: Certain diseases, such as Rett Syndrome and Turner Syndrome, exclusively or predominantly affect females. Using female-derived cell models is essential for accurate representation and study outcomes.
• Compare Findings with Female Patient-Derived Cell Lines: When studying diseases using patient-derived iPSCs, it is beneficial to have sex-matched control lines to distinguish between disease-specific effects and normal sex-based variations.
  
  

Confirming Results Across Sexes

Including both male and female iPSC lines in studies helps ensure that findings are applicable to everyone. For instance, research involving CRISPR-edited neurons with schizophrenia-associated mutations has utilized lines from both sexes to validate results (Arioka et al., 2018). This approach allows researchers to determine whether a genetic mutation has a consistent effect regardless of sex or if there are differential impacts that need to be considered in treatment strategies.

Modeling Female-Specific Conditions

For diseases that exclusively affect women, such as Rett Syndrome—a neurodevelopmental disorder caused by mutations in the MECP2 gene—using female-derived cell models is essential. Since the disease manifests differently depending on X-chromosome inactivation patterns, studying female cells provides insights into the disease mechanisms and potential therapeutic targets.

Comparative Analysis with Patient Samples

Researchers often use CRISPR to correct disease-causing variants in patient-derived iPSCs, creating isogenic controls. Incorporating healthy, sex-matched donor lines provides additional context and helps isolate the effects of specific genetic variants from normal sex-based differences. For example, swapping alleles associated with Alzheimer's disease between patient and healthy iPSC lines can help elucidate the role of specific genes in disease progression (Lin et al., 2018).

EditCo’s Contribution to Equitable Research

At EditCo, we recognize the importance of female representation in biomedical research. To support scientists in this endeavor, we have expanded our repository to include a high-quality female iPSC line reprogrammed using RNA technology, which is available for genome editing services. This female iPSC line offers researchers a reliable and consistent model for studying sex-specific differences and advancing their understanding of various diseases.

EditCo-supplied cell lines available for all engineered iPS cell orders at no additional cost

* Parental vials available for evaluation prior to booking an edit

We aim to diversify our iPSC offerings further, supporting researchers in achieving greater representation across age, sex, and ethnicity. By providing access to a broad range of iPSC lines, we enable scientists to conduct more inclusive and comprehensive studies. By doing so, we contribute to the mission of SABV and the development of inclusive therapies for the future.

Incorporating diverse genetic backgrounds into research is crucial for the discovery of treatments that are effective for everyone. EditCo is committed to facilitating this progress by supplying the tools and resources necessary for cutting-edge biomedical research.