Abstract
Hematopoietic stem cell (HSC) transplantation could be of therapeutic value for aplastic anemia (AA) patients, and immunosuppressants may facilitate the efficiency of the procedure. As anti-inflammatory cytokine interleukin-11 (IL-11) has a thrombopoietic effect, its use in cases of chronic bone marrow failure, such as AA, has been proposed to induce HSC function. However, the putative mechanisms that may support this process remain poorly defined. We found that decreased miR-204-5p levels were coincident with increased proliferation in mouse HSCs following exposure to IL-11 in vitro. Through inhibiting NF-кB activity, miR-204-5p repression was demonstrated to be a downstream effect of IL-11 signaling. miR-204-5p was shown to directly target thrombopoietin (TPO) via sequence-dependent 3′-UTR repression, indicating that this microRNA-dependent pathway could serve an essential role in supporting IL-11 functions in HSCs. Increased TPO expression in HSCs following IL-11 exposure could be mimicked or blocked by inhibiting or overexpressing miR-204-5p, respectively. Consistent with these in vitro findings, IL-11 promoted HSC engraftment in a mouse model of AA, an effect that was attenuated in cells overexpressing miR-204-5p. The reduction in miR-204-5p levels is an integral component of IL-11 signaling that may play an essential role in treating AA.
Highlights
Aplastic anemia (AA) is a severe disease characterized by bone marrow failure and is associated with defective hematopoietic stem cell (HSC) functions.[1]
The identity of cultured bone marrow derived (BM)-HSC cells was confirmed by surface markers, including CD150 positivity and CD34, CD48 and CD244 negativity (Figure 1)
The expression of thrombopoietin (TPO) in HSCs was greatly enhanced by IL-11 treatment, as shown by mRNA analysis, which was further confirmed at the protein level (Figure 2b)
Summary
Aplastic anemia (AA) is a severe disease characterized by bone marrow failure and is associated with defective hematopoietic stem cell (HSC) functions.[1] Normally, the limited lifespan of circulating blood cells necessitates a constant hematopoiesis that relies on self-renewing multipotent HSCs. Aplastic anemia (AA) is a severe disease characterized by bone marrow failure and is associated with defective hematopoietic stem cell (HSC) functions.[1] Normally, the limited lifespan of circulating blood cells necessitates a constant hematopoiesis that relies on self-renewing multipotent HSCs These cells are maintained by a specialized microenvironment in the bone marrow, and, if needed, can give rise to a hierarchy of lineagecommitted progenitor cells for massive expansion and differentiation into mature blood cells.[2] Following the destruction of HSCs, inadequately replenished hematopoietic cells, including red blood cells, white blood cells and platelets, render patients with AA at a high risk of bleeding and infection. It is clear that rescuing the immunologically stressed and depleted stem cell compartment, such as by inhibiting the CTL reaction, should serve an important role in preventing the relapse or ultimate curing the disease
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