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Peptidoglycan-Mediated Bone Marrow Autonomic Neuropathy Impairs Hematopoietic Stem/Progenitor Cells via a
Jing Wu1,2, Binghan Zhang1, Shengbing Li1
1Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Abstract:
Impairment of bone marrow-derived hematopoietic stem/progenitor cells (HSPCs) contributes to the progression of vascular complications in subjects with diabetes. Very small amounts of bacterial-derived pathogen-associated molecular patterns (PAMPs) establish the bone marrow cell pool. We hypothesize that alteration of the PAMP peptidoglycan (PGN) exacerbates HSPC dysfunction in diabetes. We observed increased PGN infiltration in the bone marrow of diabetic mice. Exogenous administration of PGN selectively reduced the number of long-term repopulating hematopoietic stem cells (LT-HSCs), accompanied by impaired vasoreparative functions in db/db mouse bone marrow. We further revealed that bone marrow denervation contributed to PGN-associated HSPC dysfunction. Inhibition of NOD1 ameliorated PGN-induced bone marrow autonomic neuropathy, which significantly rejuvenated the HSPC pools and functions in vivo. These data reveal for the first time that PGN, as a critical factor on the gut-bone marrow axis, promotes bone marrow denervation and HSPC modulation in the context of diabetes.
Insights
Bacterial peptidoglycan (PGN) worsens hematopoietic stem cell (HSC) dysfunction in diabetes, leading to vascular issues. Targeting NOD1 can restore HSC function by reducing PGN-induced nerve damage in the bone marrow.
Area of Science:
- Immunology
- Hematology
- Diabetology
Background:
- Hematopoietic stem/progenitor cells (HSPCs) impairment contributes to diabetic vascular complications.
- Bacterial pathogen-associated molecular patterns (PAMPs), like peptidoglycan (PGN), influence bone marrow cell pools.
Purpose of the Study:
- To investigate the role of peptidoglycan (PGN) in exacerbating hematopoietic stem/progenitor cell (HSPC) dysfunction in diabetes.
- To explore the link between PGN, bone marrow denervation, and HSPC modulation in diabetic conditions.
Main Methods:
- Observation of PGN infiltration in the bone marrow of diabetic mice.
- Administration of exogenous PGN to assess its effects on HSPCs and vasoreparative functions.
- Evaluation of bone marrow denervation and its contribution to PGN-induced HSPC dysfunction.
- Inhibition of NOD1 to determine its impact on PGN-induced neuropathy and HSPC rejuvenation.
Main Results:
- Increased PGN infiltration was observed in the bone marrow of diabetic mice.
- Exogenous PGN reduced long-term repopulating hematopoietic stem cells (LT-HSCs) and impaired vasoreparative functions.
- Bone marrow denervation was identified as a factor in PGN-associated HSPC dysfunction.
- NOD1 inhibition ameliorated PGN-induced bone marrow autonomic neuropathy, rejuvenating HSPC pools and functions.
Conclusions:
- PGN, acting via the gut-bone marrow axis, promotes bone marrow denervation and modulates HSPCs in diabetes.
- Targeting NOD1 offers a potential therapeutic strategy to counteract PGN-induced bone marrow damage and restore HSPC function in diabetic subjects.
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