Journal of ethnopharmacology · 2026
Ligustilide enhances TNTs-mediated mitochondrial transfer to accelerate the reactivation of TECs in sleep deprivation induced postpartum mouse.
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Shu Yaoying, Lai Xiaoyu, Xu Xie, Lu Senxu, Tao Bai, Huang Jianbo, Gao Jianli
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: Angelica sinensis (Oliv.) Diels (Danggui) has been widely used by puerperae in China for postpartum recovery for more than a thousand years. Its key active ingredient, ligustilide (LIG), has been documented to exert thymus-repairing effects; however, its role and underlying mechanisms in postpartum thymic regeneration impairment remain unclear.
AIM OF THE STUDY: During the puerperium, the acutely atrophied maternal thymus gradually returns to its non-pregnant state. However, frequent sleep deprivation (SD) resulting from neonatal breastfeeding often slows down the thymus recovery process. This study investigated the efficacy and underlying mechanism of LIG, an active ingredient of A. sinensis, against SD-induced thymic regeneration disorder (SDTRD) in postpartum mice.
MATERIALS AND METHODS: Postpartum SD was induced by automated disturbance; a progesterone-estrogen withdrawal (PE) model followed by a 7-day high-dose steroid treatment. LIG (1 mg/kg) was administered during regeneration. Thymic architecture (H&E), thymic epithelial cells (TEC) localization (immunofluorescence), and thymocyte subsets (flow cytometry) were quantified. Spleen sjTREC, thymic cytokines, and transcripts for mitochondrial biogenesis/function were measured by qPCR. TEM assessed mitochondrial ultrastructure. Dual-color mitochondrial tracing combined with a thymocyte-iTECs co-culture system and a bone-marrow-cell thymic homing assay mapped intercellular mitochondrial transfer. Tunneling nanotubes (TNTs) were disrupted with cytochalasin D; Rho-GTPase activation (including Cdc42) was evaluated.
RESULTS: Postpartum mice with SD showed damaged mitochondrial ultrastructure and reduced mitochondrial biogenesis in TECs, leading to TECs dysfunction and interruption of postpartum thymic regeneration. LIG significantly restored the abnormal spatial localization of TECs, improved the reticular framework of cortical TECs (cTECs), promoted thymocyte development, and increased output of CD4+ T-cells. Mechanistically, LIG may facilitate the formation of F-actin-dependent TNTs between thymocytes and TECs, mediating mitochondrial transfer from thymocytes to dysfunctional TECs. This process may rely on Rho GTPase signaling pathways (Cdc42 activation) to regulate F-actin polymerization.
CONCLUSIONS: LIG may promote F-actin-dependent TNTs-mediated mitochondrial transfer from thymocytes to TECs, thereby reactivating TECs, restoring the thymic microenvironment, rescuing thymocyte development and export, and ultimately ameliorating SD-induced postpartum thymic regeneration. These findings provide new experimental evidence for the development of LIG as a preventive and therapeutic intervention for defective postpartum thymic repair.
AIM OF THE STUDY: During the puerperium, the acutely atrophied maternal thymus gradually returns to its non-pregnant state. However, frequent sleep deprivation (SD) resulting from neonatal breastfeeding often slows down the thymus recovery process. This study investigated the efficacy and underlying mechanism of LIG, an active ingredient of A. sinensis, against SD-induced thymic regeneration disorder (SDTRD) in postpartum mice.
MATERIALS AND METHODS: Postpartum SD was induced by automated disturbance; a progesterone-estrogen withdrawal (PE) model followed by a 7-day high-dose steroid treatment. LIG (1 mg/kg) was administered during regeneration. Thymic architecture (H&E), thymic epithelial cells (TEC) localization (immunofluorescence), and thymocyte subsets (flow cytometry) were quantified. Spleen sjTREC, thymic cytokines, and transcripts for mitochondrial biogenesis/function were measured by qPCR. TEM assessed mitochondrial ultrastructure. Dual-color mitochondrial tracing combined with a thymocyte-iTECs co-culture system and a bone-marrow-cell thymic homing assay mapped intercellular mitochondrial transfer. Tunneling nanotubes (TNTs) were disrupted with cytochalasin D; Rho-GTPase activation (including Cdc42) was evaluated.
RESULTS: Postpartum mice with SD showed damaged mitochondrial ultrastructure and reduced mitochondrial biogenesis in TECs, leading to TECs dysfunction and interruption of postpartum thymic regeneration. LIG significantly restored the abnormal spatial localization of TECs, improved the reticular framework of cortical TECs (cTECs), promoted thymocyte development, and increased output of CD4+ T-cells. Mechanistically, LIG may facilitate the formation of F-actin-dependent TNTs between thymocytes and TECs, mediating mitochondrial transfer from thymocytes to dysfunctional TECs. This process may rely on Rho GTPase signaling pathways (Cdc42 activation) to regulate F-actin polymerization.
CONCLUSIONS: LIG may promote F-actin-dependent TNTs-mediated mitochondrial transfer from thymocytes to TECs, thereby reactivating TECs, restoring the thymic microenvironment, rescuing thymocyte development and export, and ultimately ameliorating SD-induced postpartum thymic regeneration. These findings provide new experimental evidence for the development of LIG as a preventive and therapeutic intervention for defective postpartum thymic repair.