In a nutshell:

1. Bone marrow endothelial progenitor cells (EPCs) play a crucial role in regulating hematopoietic stem cells within the bone marrow microenvironment.

2. The team led by Professor Xiaojun Huang unveils a novel mechanism – abnormal glycolysis – responsible for EPC damage and a decline in hematopoietic support capabilities. This discovery offers potential targets for precision treatment strategies post-chemotherapy, radiotherapy, and hematopoietic stem cell transplantation.

3. The study is supported by national key R&D programs and major funding from the National Natural Science Foundation.

4. Presented as an oral report at the 24th European Hematology Association Congress (EHA) and the 48th European Society for Blood and Marrow Transplantation Congress (EBMT), the findings are published in Haematologica journal.

Corresponding Authors:

– Professor Xiaojun Huang: Director of the National Clinical Research Center for Hematologic Diseases, Director of Peking University Institute of Hematology, and Chief of the Hematology Department at Peking University People’s Hospital.

– Professor Yuan Kong: Director of the Translational Center, National Clinical Research Center for Hematologic Diseases, and Deputy Director of the Key Laboratory for Hematopoietic Stem Cell Transplantation in Beijing.

First Author:

– Dr. Zhongshi Lv: Resident physician and Ph.D. candidate affiliated with the National Clinical Research Center for Hematologic Diseases, Peking University Institute of Hematology, and Peking University People’s Hospital, supervised by Professor Xiaojun Huang and co-supervised by Professor Yuan Kong.

A research team at Peking University’s Institute of Hematology has focused on “Bone Marrow Microenvironment and Hematopoietic Regulation,” conducting a series of innovative translational studies.

With the continuous improvement of allogeneic hematopoietic stem cell transplantation, the majority of patients can achieve rapid and stable hematopoietic reconstruction from donor sources. However, poor hematopoietic reconstruction after transplantation has emerged as a new and severe complication, with no effective clinical prevention and treatment measures, making it a crucial factor leading to transplant failure. Therefore, a thorough understanding of the pathogenesis of poor hematopoietic reconstruction and the establishment of novel prevention and treatment strategies are urgent challenges in the field of hematopoietic stem cell transplantation.

Since 2013, Professor Xiaojun Huang and Professor Yuan Kong, leading the team, have focused on “Bone Marrow Microenvironment and Hematopoietic Regulation,” dedicating their efforts to innovative translational research on the pathogenesis and prevention strategies of important complications such as poor hematopoietic reconstruction after transplantation. After a decade of hard work, the series of research outcomes have been included in the National “13th Five-Year Plan” Science and Technology Achievement Exhibition. The team’s work has pioneered:

(1) Abnormalities in multiple components of the bone marrow microenvironment, especially impaired hematopoietic stem cell function due to bone marrow endothelial progenitor cell (EPC) damage, were identified as significant factors leading to poor hematopoietic reconstruction after transplantation (Blood 2016, AJH 2018, STTT 2021, etc.). The journal Blood published a special review commending the team’s work: “Taking the first step from mechanistic research to treatment for implant dysfunction.”

(2) Based on the mechanistic research findings, prospective single-arm clinical trials (Blood Adv 2019) and a prospective, open-label, randomized controlled phase III clinical trial (BMC Med 2022) confirmed that: ① Bone marrow vascular endothelial cells <0.1% before transplantation are a risk factor for poor hematopoietic reconstruction after transplantation, serving as an early warning for high-risk patients; ② A novel prevention and treatment strategy for poor hematopoietic reconstruction after transplantation was created, successfully applying the ROS scavenger (NAC) in a “repurposing” approach. This intervention improved bone marrow EPC damage post-transplantation, promoting hematopoietic reconstruction in leukemia patients and partially improving transplant outcomes.

The team revealed that glycolytic dysfunction is a new mechanism for bone marrow EPC damage and the decline in their hematopoietic support capacity, providing potential new targets for treating patients with poor hematopoietic reconstruction.

The team’s earlier work suggested that bone marrow EPCs open up a new perspective on the pathogenesis and clinical research of poor hematopoietic reconstruction after transplantation. However, the molecular mechanisms of bone marrow EPC damage, especially their impaired hematopoietic support capabilities, remain important scientific questions to be addressed.

Recent research has discovered that glycolysis is the primary energy source for vascular endothelial cells, and PFKFB is the key rate-limiting enzyme in the glycolytic pathway, with PFKFB3 being predominantly expressed in endothelial cells. Abnormalities in energy metabolism, particularly PFKFB3-mediated glycolytic dysfunction, play a crucial role in proliferative vascular endothelial diseases and have potential therapeutic value. However, whether glycolysis is involved in regulating the quantity and function of bone marrow EPCs, especially their hematopoietic regulatory capabilities, needs further clarification.

On October 1, 2022, Professors Xiaojun Huang and Yuan Kong, from Peking University People’s Hospital, Peking University Institute of Hematology, and the National Clinical Research Center for Blood Diseases, published a research paper titled “Glycolytic enzyme PFKFB3 determines bone marrow endothelial progenitor cell damage post chemotherapy and irradiation” in the journal Haematologica. The paper reveals a new mechanism for bone marrow vascular endothelial progenitor cell damage and proposes targeted repair strategies.

Through prospective clinical cohort studies, the research found that the key enzyme PFKFB3 in the glycolytic pathway is abnormally highly expressed in damaged bone marrow EPCs of patients with poor hematopoietic reconstruction post-transplantation compared to patients with good hematopoietic reconstruction and healthy individuals. Further confirmation was provided through in vitro models of bone marrow EPC injury, mouse models of bone marrow hematopoietic injury caused by radiation or chemotherapy, and mouse models with specific overexpression of PFKFB3 in bone marrow vascular endothelial cells. The study confirmed that PFKFB3-induced glycolytic dysfunction leads to functional damage of bone marrow EPCs, inhibiting their hematopoietic support capacity. Conversely, inhibiting PFKFB3 can repair the functional damage of bone marrow EPCs and improve their hematopoietic support capacity. The results suggest that abnormal activation of the glycolytic key enzyme PFKFB3 is a new mechanism leading to bone marrow EPC damage and the decline in their hematopoietic support capacity. It represents a potential new therapeutic target for targeted repair of EPCs. Regarding the mechanism by which PFKFB3 causes bone marrow EPC damage, the study first discovered that PFKFB3 upregulates the expression of the apoptosis-inducing transcription factor FOXO3A and its downstream apoptotic molecules, causing bone marrow EPC damage. Additionally, PFKFB3 activates the NF-κB pathway in bone marrow EPCs, promoting the expression of the adhesion molecule E-selectin downstream and reducing the expression of the hematopoietic factor SDF-1, thereby reducing the hematopoietic support capacity of EPCs.

Therefore, this study integrates clinical case resources, in vitro experiments, and mouse models to reveal glycolytic dysfunction as a new mechanism for bone marrow EPC functional damage. Inhibitors of glycolysis can repair bone marrow EPC damage and improve their hematopoietic support capacity. Thus, the glycolytic pathway of bone marrow EPCs is expected to become a potential new therapeutic target for patients with poor hematopoietic reconstruction.

Researchers’ Analysis:

Poor hematopoietic reconstruction after transplantation is not only a significant factor leading to the failure of hematopoietic stem cell transplantation but also an ideal model for studying the regulation of hematopoietic damage. Building on previous series of works, this study first revealed: ① Abnormal activation of the glycolytic key enzyme PFKFB3 is a new mechanism leading to bone marrow EPC damage and the decline in their hematopoietic support capacity, contributing to the occurrence of chemotherapy, radiotherapy, and poor hematopoietic reconstruction after transplantation; ② PFKFB3 induces glycolytic dysfunction, leading to bone marrow EPC damage by regulating the expression of apoptosis and inflammation-related molecules mediated by FOXO3A and reducing the expression of the hematopoietic regulatory factor SDF-1; ③ PFKFB3 inhibitors can repair bone marrow EPC damage, promoting hematopoietic repair post-chemotherapy, radiotherapy, and transplantation. In summary, this study reveals new mechanisms for bone marrow EPC damage and targeted repair strategies, providing new targets for the precise prevention and treatment strategies based on the pathogenesis of patients with poor hematopoietic reconstruction after chemotherapy, radiotherapy, and hematopoietic stem cell transplantation. It has significant value for clinical translational applications.

Reference :

Lyu ZS, Tang SQ, Xing T, Zhou Y, Lv M, Fu HX, Wang Y, Xu LP, Zhang XH, Lee HY, Kong Y*, Huang XJ*. Glycolytic enzyme PFKFB3 determines bone marrow endothelial progenitor cell damage post chemotherapy and irradiation. Haematologica. 2022; 107(10):2365-2380.