Sertoli cells are the maestros of testicular architecture and sentinels of germ cell development. First described by Enrico Sertoli in 1865, these elongated somatic cells reside within the seminiferous tubules of the testes. Although initially underappreciated, decades of research have revealed their central role in male reproductive biology. Far from oblivious bystanders, sertoli cells provide structural support, construct an immune barrier, and secrete signaling molecules that guide spermatozoa development. Fundamental research into sertoli cell organization [1], the identification and definition of the secondary sex tissues’ role in sex determination [2], and the lineage-tracing work [3] have aided in defining Sertoli cells not just as “nurse cells,” but as the conductors of spermatogenic symphony.
The Architects of the Testis
Lining the seminiferous tubule walls, these specialized somatic cells construct the microenvironment where sperm are born. Both sentinels and scaffolding also help organize germ cells in an extremely ordered, layered manner, one analogous to temporal and spatial choreography of spermatogenesis. The blood-testis barrier (BTB), a tight junctional complex between adjacent Sertoli cells, compartmentalizes the seminiferous epithelium into adluminal and basal regions. This organization protects developing germ cells from immune surveillence and restricts molecular permeation to ensure Sertoli cells regulate what enters the germ cell microenvironment [4–6].
The Sustainers of Spermatogenesis
Spermatogenesis is metabolically costly, tightly controlled, and depends upon Sertoli cells for more than protection. They carry lactate, transferrin, and other nutrients to germ cells. They phagocytose the residual cytoplasm of forming spermatids and respond to hormonal cues like FSH and testosterone to synchronize their actions with the requirements of germ cells [1, 7]. Experiments using genetic and hormonal manipulation in rodent models have helped define how FSH regulates Sertoli cell transcriptional networks to initiate and sustain spermatogenesis [1]. These studies show that FSH promotes Sertoli cell proliferation and modulates gene expression critical for germ cell support. Related research has also provided insight into Sertoli cell behavior in testicular organoid systems, where dissociated neonatal testis cells self-organize into seminiferous tubule–like structures capable of supporting germ cell development up to the meiotic phase [8].
Censors of Immunological Intruders
Among their most fascinating roles, Sertoli cells help maintain the testes as an immune-privileged site — a biological environment where immune responses are actively suppressed to protect developing germ cells. Because these germ cells arise postnatally, they may be recognized as “non-self” by the immune system, making them vulnerable to autoimmune attack. To prevent this, Sertoli cells establish the blood-testis barrier (BTB) and secrete immunosuppressive factors that shield germ cells from immune surveillance [6, 9].
This unique immunological environment has made Sertoli cells a promising tool in transplantation research, where their protective properties are being explored for promoting graft tolerance beyond the reproductive system [9]. However, exposure to environmental toxins can disrupt this immunoprotection, posing long-term risks to male fertility [10].
Hormonal Command Center
Deeply embedded in the endocrine regulation of the male reproductive axis, these somatic cells don’t act alone. They both possess androgen receptors and FSH receptors, enabling them to respond dynamically to hormone cues. Upon FSH binding, Sertoli cells modify gene expression to facilitate germ cell survival, and testosterone fine-tunes it with paracrine signaling [1, 11]. This has been advanced by researchers showing how sensitivity of Sertoli cells to these hormones is modified by epigenetic modifiers — another level of regulatory complexity added [12].
Unraveling the Unknowns
From organoid systems to fertility preservation, the limelight is on Sertoli cells regarding reproductive biology. Studies continue to be centered on investigating early genetic switches, such as SOX9, that fix the fate of progenitor cells towards the Sertoli fate [2]. Meanwhile, scientists lead global efforts to reconstitute the spermatogenic niche in vitro, opening doors to novel therapies for cancer patients and azoospermic individuals [8]. Even early studies have revealed that Sertoli cell function and broader testicular physiology are influenced by circadian clock genes. In BMAL1 knockout mice, disrupted rhythmic expression of steroidogenic genes like StAR led to impaired testosterone production and infertility, underscoring the role of circadian regulation in male reproductive function [13].
The Unsung Heroes of the Testis
Though they cannot be seen with a naked eye, Sertoli cells are accountable for the visible outcome of male fertility. From orchestrating germ cell development to offering protection to the testis against invasion by the immune system, they are miracle-working multitaskers [14]. As labs worldwide continue to unravel their secrets, Sertoli cells are emerging into the scientific spotlight — not merely as supporting cells, but as the magnificoes of reproductive order.
Recognizing and appreciating the labs working in this space
- Griswold Lab: Washington State University, WA, USA. https://labs.wsu.edu/griswold-lab/
- Wolgemuth Lab: Columbia University Medical Center, NY, USA. https://www.ihn.cuimc.columbia.edu/profile/debra-j-wolgemuth-phd
- Behringer Lab: MD Anderson Cancer Center, TX, USA. https://www.mdanderson.org/research/departments-labs-institutes/labs/behringer-laboratory.html , X: @rrbehringer
- Yao Lab: NIH, National Institute of Environmental Health Sciences, USA. https://www.niehs.nih.gov/research/atniehs/labs/rdbl/pi/developmental
- Dufour Lab: Texas Tech University Health Sciences Center, TX, USA. https://www.ttuhsc.edu/medicine/cell-biology-biochemistry/faculty/dufour.aspx , FB: https://www.facebook.com/ttuhsc/ , IG: @ttuhsc , LinkedIn: https://www.linkedin.com/school/texas-tech-university-health-sciences-center/ , X: @TTUHSC
- Toppari Lab: University of Turku, Finland. https://www.utu.fi/en/people/jorma-toppari
- Koopman Lab: University of Queensland, Australia. https://imb.uq.edu.au/profile/464/peter-koopman , FB:https://www.facebook.com/uniofqldinternational/?brand_redir=137474816330115# , LinkedIn: https://www.linkedin.com/school/university-of-queensland/ , X: @uq_news
- Kimmins Lab: McGill University, Montreal, Canada. https://www.chumontreal.qc.ca/en/crchum/chercheurs/sarah-kimmins , X: @KimminsSarah , Linkedin: https://www.linkedin.com/in/sarah-kimmins-33004970/
- Sassone-Corsi Center (Legacy Work): University of California, Irvine, USA. https://cempschome.wordpress.com/meet-the-lab/ , X: @sassonecorsilab
- Schlatt Lab: Centre of Reproductive Medicine and Andrology (CeRA), University of Münster, Germany. https://www.medizin.uni-muenster.de/en/cera/research/spermatogenesis-and-testis-function-schlatt/research-focus.html
References
- Griswold MD. The central role of Sertoli cells in spermatogenesis. Semin Cell Dev Biol. 1998;9(4):411–416.
- Koopman P, Munsterberg A, Capel B, Vivian N, Lovell-Badge R. Expression of a candidate sex-determining gene during mouse testis differentiation. Nature. 1990;348(6300):450–452.
- Yao HH, Capel B. Disruption of testis cords by cyclopamine or forskolin reveals independent cellular pathways in testis organogenesis. Dev Biol. 2002;246(2):356–365.
- Cheng CY, Mruk DD. The blood-testis barrier and its implications for male contraception. Pharmacol Rev. 2012;64(1):16–64.
- Mruk DD, Cheng CY. The mammalian blood-testis barrier: its biology and regulation. Endocr Rev. 2015;36(5):564–591.
- Dufour JM, Rajotte RV, Seeberger K, Kin T, Korbutt GS. Long-term survival of neonatal porcine Sertoli cells in non-immunosuppressed rats. Xenotransplantation. 2003;10(6):577–586.
- Oatley JM, Brinster RL. Regulation of spermatogonial stem cell self-renewal in mammals. Annu Rev Cell Dev Biol. 2008;24:263–286.
- Yokonishi T, Sato T, Katagiri K, Komeya M, Kubota Y, Ogawa T. In Vitro Reconstruction of Mouse Seminiferous Tubules Supporting Germ Cell Differentiation. Biol Reprod. 2013;89(1):15.
- Dufour JM, Dass B, Halley KR, Korbutt GS, Dixon DE, Rajotte RV. Sertoli cell line lacks the immunoprotective properties associated with primary Sertoli cells. Cell Transplant. 2008;17(5):525–534.
- Toppari J, Virtanen HE, Main KM, Skakkebaek NE. Cryptorchidism and hypospadias as a sign of testicular dysgenesis syndrome (TDS): environmental connection. Birth Defects Res A Clin Mol Teratol. 2010;88(10):910–919.
- Walker WH, Cheng J. FSH and testosterone signaling in Sertoli cells. Reproduction. 2005;130(1):15–28.
- Shea JM, Serra RW, Carone BR, et al. Genetic and Epigenetic Variation, but Not Diet, Shape the Sperm Methylome. Dev Cell. 2015;35(6):750–758.
- Alvarez JD, Hansen A, Ord T, et al. The circadian clock protein BMAL1 is necessary for fertility and proper testosterone production in mice. J Biol Rhythms. 2008;23(1):26–36.
- Gu W, Gaeta X, Sahakyan A, et al. Glycolytic Metabolism Plays a Functional Role in Regulating Human Pluripotent Stem Cell State. Cell Stem Cell. 2016;19(4):476–490.
About the author:
DR. CHRISTY KESTNER
Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Christy Kestner holds a PhD in Neuroimmunology from the Medical University of South
Carolina (MUSC), where she studied how complement drives pathological conditions related to neuroinflammation and brain injury (stroke and traumatic brain injury), as well as approaches to reduce harmful complement activation. She later conducted postdoctoral research in oncology therapeutic development, investigating new drug targets for pancreatic cancer. Dr. Kestner currently works as a scientific and medical writer, creating educational content and op-eds for science and health communication platforms. She also runs her own science communication platform, Brain & Beyond, aimed at translating complex research into accessible content. Passionate about science storytelling, she is dedicated to making immunology and neuroscience both accurate and engaging for diverse audiences.
About the artist:
RENSKE HOSTE
Contributing Artist The League of Extraordinary Cell Types, Sci-Illustrate Stories
Renske is a professional medical artist who spends most of her time working on anatomy and pathology in 2D and 3D. She joined as a creator of the League of Extraordinary Cell Types to challenge herself to combine science with her love for art and all things nature and growing. When not working full-time or as a freelancer, Renske loves growing things in her garden, kicking butt doing Krav Maga, or being knee-deep in various creative projects.
About the animator:
DR. EMANUELE PETRETTO
Animator The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Petretto received his Ph.D. in Biochemistry at the University of Fribourg, Switzerland, focusing on the behavior of matter at nanoscopic scales and the stability of colloidal systems. Using molecular dynamics simulations, he explored the delicate interaction among particles, interfaces, and solvents.
Currently, he is fully pursuing another delicate interaction: the intricate interplay between art and science. Through data visualization, motion design, and games, he wants to show the wonders of the complexity surrounding us.
About the series:
The League of Extraordinary Cell types
The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.
