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Lysophosphatidic Acid Signaling Through LPA2 Suppresses Apoptosis of Spermatogenic Cells
Kuniyuki Kano1, Takumi Sugawara2, and Junken Aoki11 Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan,
2 Graduate School of Pharmaceutical Sciences, Tohoku University, Japan
Background and Aims: Spermatogenic cells are susceptible to apoptosis under various stress conditions, leading to the loss of sperm production. The lysophosphatidic acid receptors, LPA1, LPA2, and LPA3, are highly expressed in the testis. Previously, LPA1/2/3 triple deficient mice were reported to develop severe testicular degenerative changes with azoospermia1, suggesting that these three LPA receptors have a redundant role in testicular homeostasis and sperm production. However, the specific contributions of each LPA receptor in sperm production and the underlying mechanism remain to be determined. Here we report an anti-apoptotic role of LPA2 signaling in spermatids.
Method and Results: We found that LPA2 was widely expressed in spermatogenic cells, and LPA2 single deficiency led to spontaneous testicular degeneration characterized by the appearance of the vacuoles. In the testicular ischemia-reperfusion model, LPA2 deficiency resulted in increased TUNEL-positive spermatogenic cells. Conversely, the administration of an LPA2 agonist significantly improved testicular apoptosis. Our MS imaging analysis based on the derivatization method using a Phos-tag2 revealed that palmitoyl LPA, a good ligand for LPA2, was confined in the inner seminiferous tubules expressing LPA2 and autotaxin (ATX). Notably, palmitoyl LPA and LPC were upregulated in the testicular ischemia model. We previously demonstrated that human seminal plasma contained abundant LPA, which sufficiently activated LPA receptors3. In this study, we also found a significant correlation between sperm concentration and the level of ATX in seminal fluids from patients with infertility, suggesting that ATX-LPA signaling is an important factor in spermatogenesis in humans.
Conclusions: These results lead to our presumption that the ATX-LPA-LPA2 axis determines sperm concentration by suppressing the apoptosis of spermatogenic cells. Furthermore, LPA2 signaling could be a promising new therapeutic target for male infertility caused by low sperm density.
References
1 X, Ye. et al., Biol. Reprod. 79, 328–336 (2008).
2 T, Iwama. et al., Ana Chem. 93, 8, 3867–3875 (2021)
3 Hama, K. et al., FEBS Lett. 523, 187–192 (2002).
Speakers
Kuniyuki Kano