pDCs on Patrol and in Control of Megakaryopoiesis

Megakaryocyte homeostasis is controlled by passive and active mechanisms, locally and systemically, by thrombopoietin (TPO) together with collaborating growth factors. TPO was originally thought to be produced at a constant level, with the liver as the primary source, and TPO levels passively determined by megakaryocyte/platelet mass and the degree of “sponging” from plasma via the TPO receptor.¹  Subsequently, it was shown that hepatic TPO synthesis is dynamic, stimulated by clearance of aged, desialylated platelets via the Ashwell-Morell receptor.²  TPO is also synthesized in the local tissue environment by bone marrow stromal cells, where the rate of synthesis is influenced by thrombocytopenia as well as inflammatory signals.¹  In 2021, Melissa M. Lee-Sundlov, PhD, and colleagues introduced the concept that innate immune cells such as plasmacytoid dendritic cells (pDCs) regulate platelet production by patrolling for aberrant expression of sialic acids on the megakaryocyte cell surface.³  This July, a seminal paper by Florian Gaertner, MD, PhD, and colleagues added a new angle for how megakaryocyte and platelet production is controlled at local tissue level.

Dr. Gaertner and his team use in vivo imaging to provide beautiful videographic evidence that megakaryocytes migrate to sinusoids before enlarging in size and producing platelets. They observed that once a megakaryocyte enters thrombopoiesis, it disintegrates within hours but is rapidly replaced. This finding led them to hypothesize that “vanishing” megakaryocytes trigger their own replenishment. Mature megakaryocytes have a supranormal DNA content, with an average ploidy of 16N in humans. Megakaryocytes were also recently recognized as major contributors to cell-free DNA in blood plasma.⁴  Dr. Gaertner and colleagues explored whether innate immune cells might respond to megakaryocyte apoptosis via nucleic acid sensing pathways. They showed that pDCs, cells which are highly motile in the bone marrow, are found in close proximity to megakaryocytes, and that depleting pDCs in mice led to a 50% reduction in mature megakaryocytes and a 25% reduction in megakaryocyte progenitors, with an expected drop in platelet production. Exposing pDCs to apoptotic megakaryocytes ex vivo triggered the release of high amounts of interferon-alpha (IFN-α), an effect blocked by adding deoxyribonuclease to the cultures, confirming that pDCs were responding to DNA release. IFN-α and TPO acted synergistically to promote megakaryopoiesis in vitro.

The researchers also showed that pDC-megakaryocyte interactions occur in human bone marrow, with evidence of a role in disease settings. They identified higher pDC-megakaryocyte contacts in both patients with immune thrombocytopenia and in severe COVID-19 infection, suggesting a role for pDCs in the megakaryocyte hyperplasia observed in autoimmunity and viral infections.