in the bone marrow
New research has revealed a mechanism through which hematopoietic stem and progenitor cells (HSPCs) control both their own proliferation and the characteristics of the niche that houses them.
Researchers detected high expression of the protein E-selectin ligand-1 (ESL-1) in HSPCs and also found that ESL-1 controls HSPCs’ production of the cytokine TGF-β.
The team said this is important because TGF-β has antiproliferative properties and is essential for impeding the loss of HSPCs in some diseases, such as some types of anemia.
The researchers also showed that HSPCs lacking ESL-1 are resistant to chemotherapeutic and cytotoxic agents.
These results suggest ESL-1 is a potential target for therapies aimed at improving bone marrow regeneration after chemotherapy or for expanding the HSPC population in preparation for donation.
Magdalena Leiva, PhD, of Centro Nacional de Investigaciones Cardiovasculares in Madrid, Spain, and her colleagues reported these findings in Nature Communications.
The researchers first found that ESL-1 deficiency causes HSPC quiescence and expansion, and elevated TGF-β causes quiescence in the absence of ESL-1. In addition, ESL-1 controls HSPC proliferation independently of E-selectin, and HSPCs are a relevant source of TGF-β.
The team also discovered that ESL-1 exerts local effects on distinct cell populations in the stromal niche. They found that hematopoietic-borne ESL-1 can control HSPC proliferation directly through cytokine secretion, and/or indirectly through repressive effects on supportive niche cells.
According to Dr Leiva, this finding opens the path to new therapies “that use genetically modified stem cells to treat hematological diseases, such as certain types of leukemia, in which the hematopoietic niche and HSPCs are very affected.”
The researchers made these discoveries by analyzing the bone marrow of mice deficient in ESL-1. In the absence of ESL-1, HSPCs proliferated less and were therefore of superior quality and more suitable for potential therapeutic applications, the team found.
“We see that these cells are resistant to processes associated with bone marrow damage, such as cell death triggered by cytotoxic agents,” Dr Leiva said.
She and her colleagues found that stem cells lacking ESL-1 were resistant to the deleterious effects of 5-fluorouracil and hydroxyurea. They said this suggests ESL-1 is a possible therapeutic target for improved regeneration of the bone marrow during chemotherapy.
