Impaired hematopoietic stem cell (HSC) self-renewal in β-thalassemia is induced by an altered bone marrow microenvironment and correction of HSC-stromal niche crosstalk rescues thalassemic HSC function by in vivoreactivation of PTH signaling, according to a study published in Blood.
HSCs in the adult hematopoietic system are regulated by signals from the bone marrow niche; however, few studies have robustly investigated malignancies in which the homeostasis of bone marrow is compromised when HSCs are not directly affected.
In β-thalassemia, ineffective erythropoiesis and secondary alterations such as abnormal regulation of bone metabolism, iron overload, and hormonal factors induce changes in the bone marrow homeostasis with a potential effect on HSC-niche interaction.
A team of researchers in Italy investigated the molecular causes of these unexplored effects on HSC by observing Hbb gene function in mice with thalassemia (th3) and comparing these findings in pretransplant donors and eligible candidates for bone marrow transplantation.
Both stromal and hematopoietic components of the bone marrow niche were altered in th3 mice. HSC in th3 mice resulted in loss of quiescence, a reduction in cell frequency, and a lower posttransplantation reconstituting capacity. At a cellular and molecular level, bone marrow stromal niche was defective. th3 HSC had impaired self-renewal, which was rescued upon transplantation in a normal bone marrow, proving an active role of the niche microenvironment.
Consistent with previous finding of osteoporosis in patients, the investigators found that lower bone mass in adult th3 mice was related to the reduced levels of parathyroid hormone (PTH), a key regulator of bone metabolism and HSC activity. Low PTH levels negatively affect bone deposition and expression of the Jag1, which is responsible for producing JAG1, a Notch ligand involved in regulating HSC maintenance. Administration of PTH in vivo reestablished JAG1 levels, thus repairing the HSC-stromal niche crosstalk, which corrected function in thalassemic HSCs.
The authors concluded that their findings “uncover a defect of HSCs in β-thalassemia induced by an altered [bone marrow] niche and provide new relevant insight for improving transplantation and gene therapy approaches.”
Further investigation will unravel the multiple molecular mechanisms that affect transplanted HSC functions associated with a stressed thalassemic bone marrow microenvironment.
Aprile A, Guliono A, Storto M, et al. Hematopoietic stem cell function in β-thalassemia is impaired and is rescued by targeting the bone marrow niche [published online April 28, 2020]. Blood. doi: 10.1182/blood.2019002721.