Tetrahydroxy stilbene glucoside rejuvenates aging hematopoietic stem cells with predilection for lymphoid differentiation via AMPK and Tet2

期刊名：Journal of Advanced Research

文章地址：https://doi.org/10.1016/j.jare.2024.04.027

Abstract

Introduction

Aging of hematopoietic stem cells (HSCs) has emerged as an important challenge to human health. Recent advances have raised the prospect of rejuvenating aging HSCs via specific medical interventions, including pharmacological treatments. Nonetheless, efforts to develop such drugs are still in infancy until now.

Objectives

We aimed to screen the prospective agents that can rejuvenate aging HSCs and explore the potential mechanisms.

Methods

We screened a set of natural anti-aging compounds through oral administration to sub-lethally irradiated mice, and identified 2,3,5,4′-tetrahydroxystilbene-2-O-β-D-glucoside (TSG) as a potent rejuvenating agent for aging HSCs. Then naturally aged mice were used for the follow-up assessment to determine the HSC rejuvenating potential of TSG. Finally, based on the transcriptome and DNA methylation analysis, we validated the role of the AMP-activated protein kinase (AMPK)-ten-eleven-translocation 2 (Tet2) axis (the AMPK-Tet2 axis) as the underlying mechanisms of TSG for ameliorating HSCs aging.

Results

TSG treatment not only significantly increased the absolute number of common lymphoid progenitors (CLPs) along with B lymphocytes, but also boosted the HSCs/CLPs repopulation potential of aging mice. Further elaborated mechanism research demonstrated that TSG supplementation restored the stemness of aging HSCs, as well as promoted an epigenetic reprograming that was associated with an improved regenerative capacity and an increased rate of lymphopoiesis. Such effects were diminished when the mice were co-treated with an AMPK inhibitor, or when it was performed in Tet2 knockout mice as well as senescent cells assay.

Conclusion

TSG is effective in rejuvenating aging HSCs by modulating the AMPK- Tet2 axis and thus represents a potential candidate for developing effective HSC rejuvenating therapies.

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Mouse models and treatments

To screen a library of natural anti-aging compounds on radiation induced premature aging of the hematopoietic system, 8-week-old C57BL/6J mice were subjected to either sham irradiation as controls or a sublethal 4 Gy dose of X-ray radiation (RS2000XE, Rad Source) for total body irradiation (TBI), with a dose rate of 0.4 Gy/min. After TBI treatment, the mice were treated with either vehicle (saline) or compound solutions. All following compounds were administered at the various doses (mg per kg body weight per day (mg/kg/d)) as the following: astragaloside Ⅳ at 50 mg/kg/d, berberine at 100 mg/kg/d, cordycepin at 100 mg/kg/d, emodin at 30 mg/kg/d, ferulic acid at 100 mg/kg/d, ginsenoside Rg1 at 60 mg/kg/d, icariin at 50 mg/kg/d, notoginsenoside R1 at 30 mg/kg/d, and tetrahydroxy stilbene glucoside (TSG) at 120 mg/kg/d were administered to the TBI mice by gavage for 60 days, respectively. Subsequently, aging C57BL/6J mice received TSG orally at a dosage of 120 mg/kg/day for 60 days, while 5-aminoimidazole-4-carboxamide riboside (AICAR, absin, abs812834, China) was administered intraperitoneally at a dose of 50 mg/kg daily for the same period. The administration of compound C (Com C, Selleck, S7306, USA) at 10 mg/kg intraperitoneally every alternate day was followed by TSG oral dosing. 40-week-old Tet2 Mut mice displayed a more evident CLP decrease and skewed myeloid/lymphoid ratio than 16 weeks of age[13]. Tet2 Mut mice at 40-week-old were treated with vehicle (saline) or TSG solution by gavage for 60 days, respectively. All natural compounds were sourced from Chengdu Pufei De Biotech Co., Ltd., China. Each experiment consisted of 4 mice per group, and mice were sacrificed to analyze as described below. All experiments were replicated a minimum of three times.