Hematopoietic stem cells (HSCs) respond to increased hematopoietic demands by supporting red blood cell production. This activation occurs during blood loss, radiation exposure, chemotherapy, bacterial infections, and pregnancy.
During pregnancy, estrogen stimulates HSC activity, increasing their division and supporting extramedullary erythropoiesis in the spleen, which helps prevent anemia. However, this alone does not fully explain HSC activation and extramedullary hematopoiesis after significant blood loss.
Retrotransposons, a subset of transposons capable of moving within the genome via RNA intermediates, have known roles in immune regulation and interferon expression, yet their involvement in adult hematopoiesis is poorly understood. Researchers investigated how retrotransposons and the cGAS-STING pathway influence HSC activation and erythropoiesis during pregnancy and other hematopoietic stress events.
Pregnancy Triggers Retrotransposon Activation in HSCs
In pregnant mice, retrotransposons, including LINE and endogenous retroviruses, were highly expressed in splenic but not bone marrow HSCs. In non-pregnant mice, there was no significant retrotransposon expression in HSCs.
Similarly, pregnant women exhibited increased retrotransposon expression (LINE and SINE). Genes related to erythropoiesis and immune responses, including several interferon-regulated genes, were activated. HSCs with higher LINE and SINE expression displayed pronounced interferon-regulated gene activity compared to those with low retrotransposon expression.
Estrogen’s Partial Role in Retrotransposon Activation
Administering estradiol (2 μg/day for six days) in mice boosted HSC division in the bone marrow and spleen and increased splenic erythropoiesis. Estradiol also elevated retrotransposon expression in splenic HSCs, albeit less significantly in bone marrow HSCs. However, retrotransposon levels during estradiol treatment were much lower than those observed during pregnancy, suggesting additional regulatory mechanisms.
Retrotransposon Activation After Blood Loss
Following blood loss, splenic HSCs exhibited enhanced expression of erythropoiesis-related genes compared to bone marrow HSCs. As seen in pregnancy, retrotransposons were highly expressed in splenic HSCs post-blood loss, confirming their critical role in hematopoietic stress responses.
Antiretroviral Drugs Suppress Erythropoiesis
Reverse transcriptase inhibitors, such as tenofovir and emtricitabine, are antiretroviral drugs that inhibit the replication of the human immunodeficiency virus (HIV). In non-pregnant mice, reverse transcriptase inhibitors had little effect on blood counts and bone marrow and spleen HSCs. However, reverse transcriptase inhibitors in pregnant mice reduced red blood cell counts without affecting white blood cell and platelet counts, reducing bone marrow cellularity and spleen HSC frequency. Reverse transcriptase inhibitors decreased the rate of HSC division in the bone marrow and spleen of pregnant mice.
Decreasing the frequency of HSCs in the spleen, but not in the bone marrow, decreased the regenerative activity of spleen cells, not bone marrow cells. Thus, reverse transcription was required to increase HSC division erythropoiesis in the spleen and maintain average RBC numbers during pregnancy.
Pregnant women treated with reverse transcriptase inhibitors had decreased hemoglobin levels, leading to anemia. HSCs from these women showed significantly fewer changes in IFN-regulated gene expression than HSCs from women not taking reverse transcriptase inhibitors, even when considering only HSCs with high LINE and SINE expression.
The Role of cGAS-STING in Erythropoiesis
STING protein was activated in bone marrow and spleen HSCs in pregnant mice. Reverse transcriptase inhibitors reduced STING activation in the spleen.
In non-pregnant mice, STING deficiency did not affect blood parameters and bone marrow and spleen HSCs. STING deficiency also did not affect the rate of HSC division or the regenerative potential of bone marrow and spleen cells.
cGAS deficiency had virtually no effect on the number of blood cells, bone marrow, and spleen cellularity or the frequency of HSCs in bone marrow and spleen. cGAS deficiency also did not affect the rate of HSC division or the regenerative potential of bone marrow and spleen cells.
In pregnant mice, STING deficiency reduced red blood cell counts but not white blood cells or platelets. STING deficiency did not reduce bone marrow and spleen cellularity but significantly reduced splenic HSC frequency, bone marrow and spleen HSC division rate, and bone marrow and spleen cell regenerative potential.
cGAS deficiency reduced red blood cell counts but not leukocyte and platelet counts. cGAS deficiency did not reduce bone marrow and spleen cellularity but reduced splenic HSC frequency, splenic HSC division rate, and spleen cell regenerative potential bone marrow.
Thus, cGAS-STING activation promoted increased splenic HSC proliferation and erythropoiesis during pregnancy, while cGAS and STING deficiency decreased red blood cell counts in pregnant mice.
Interferons and Their Role in Erythropoiesis
cGAS-STING activation promotes type I interferon (IFN-α) production in HSCs during pregnancy. Acute increases in IFN-α enhance HSC proliferation, while chronic IFN-α production depletes HSC populations. Pregnant mice showed elevated IFN-α levels in the bone marrow and spleen but not in plasma.
In mice, pregnancy increased IFN-α levels in bone marrow and spleen but not in plasma. IFN-γ signaling was also increased in HSCs but not systemically during pregnancy. Increased IFN-α levels led to cGAS-STING, especially in the spleen. STING is required for most IFN-regulated gene expression changes activated in HSCs during pregnancy. However, in other bone marrow and spleen cells, STING suppresses IFN responses.
Type I interferons supported splenic erythropoiesis during pregnancy. However, mice lacking Ifnar1 did not exhibit reduced red blood cell counts, suggesting alternative mechanisms in cGAS-STING-mediated erythropoiesis, potentially involving type II interferons.
Conclusion
During pregnancy, retrotransposons are activated in HSCs, triggering the cGAS-STING signaling pathway and an interferon response that enhances HSC activity and erythropoiesis. These mechanisms help maintain red blood cell levels, preventing anemia during pregnancy and other hematopoietic stress events. Suppressing retrotransposons with antiretroviral drugs disrupts this process, particularly in pregnant individuals, leading to anemia by inhibiting innate immune activation pathways.
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Reference
Retrotransposons are co-opted to activate hematopoietic stem cells and erythropoiesis
