TY - JOUR
T1 - Murine bone marrow mesenchymal stromal cells have reduced hematopoietic maintenance ability in sickle cell disease
AU - Tang, Alice
AU - Strat, Ana Nicolle
AU - Rahman, Mahmudur
AU - Zhang, Helen
AU - Bao, Weili
AU - Liu, Yunfeng
AU - Shi, David
AU - An, Xiuli
AU - Manwani, Deepa
AU - Shi, Patricia
AU - Yazdanbakhsh, Karina
AU - Mendelson, Avital
N1 - Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/12/16
Y1 - 2021/12/16
N2 - Sickle cell disease (SCD) is characterized by hemolytic anemia, which can trigger oxidative stress, inflammation, and tissue injury that contribute to disease complications. Bone marrow mesenchymal stromal cells (MSCs) tightly regulate hematopoietic stem cell (HSC) homeostasis in health and disease, but their functionality in SCD remains unclear. We identified for the first time that murine SCD MSCs have altered gene signatures, reduced stem cell properties, and increased oxidative stress, due in part to hemolysis. Murine SCD MSCs had lower HSC maintenance ability in vitro and in vivo, as manifested by increased HSC mobilization and decreased HSC engraftment after transplant. Activation of Toll-like receptor-4 through p65 in MSCs further contributed to MSC dysfunction. Transfusions led to an improved MSC and HSC oxidative state in SCD mice. Improving the regulation between MSCs and HSCs has vital implications for enhancing clinical HSC transplantation and gene therapy outcomes and for identification of new molecular targets for alleviating SCD complications.
AB - Sickle cell disease (SCD) is characterized by hemolytic anemia, which can trigger oxidative stress, inflammation, and tissue injury that contribute to disease complications. Bone marrow mesenchymal stromal cells (MSCs) tightly regulate hematopoietic stem cell (HSC) homeostasis in health and disease, but their functionality in SCD remains unclear. We identified for the first time that murine SCD MSCs have altered gene signatures, reduced stem cell properties, and increased oxidative stress, due in part to hemolysis. Murine SCD MSCs had lower HSC maintenance ability in vitro and in vivo, as manifested by increased HSC mobilization and decreased HSC engraftment after transplant. Activation of Toll-like receptor-4 through p65 in MSCs further contributed to MSC dysfunction. Transfusions led to an improved MSC and HSC oxidative state in SCD mice. Improving the regulation between MSCs and HSCs has vital implications for enhancing clinical HSC transplantation and gene therapy outcomes and for identification of new molecular targets for alleviating SCD complications.
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U2 - 10.1182/blood.2021012663
DO - 10.1182/blood.2021012663
M3 - Article
C2 - 34329381
AN - SCOPUS:85121147591
SN - 0006-4971
VL - 138
SP - 2570
EP - 2582
JO - Blood
JF - Blood
IS - 24
ER -