Author ORCID Identifier
Year of Publication
Doctor of Philosophy (PhD)
Molecular and Cellular Biochemistry
Dr. Sidney Whiteheart
The role of megakaryocytes in biology has long been restricted to platelet production. Recent findings have challenged this assumption by demonstrating that megakaryocytes are tightly involved in the maintenance and overall health of stem cell niches in the bone marrow. They are vital to the health of these niches and participate in this process through the localized release of growth factors and cytokines. Many of these factors are also stored within the alpha-granule of MKs as they develop, ultimately being secreted by platelets once in circulation. We have previously characterized platelets from serglycin (SRGN) null mice and found that the alpha-granules from these platelets were deficient in the levels of several cytokines. SRGN is a unique intracellular proteoglycan that is expressed by all hematopoietic cells and some other cell types. It is typically stored within secretory granules, and then released when the cell is activated. SRGN-/- platelet alpha-granules had only 10% of the normal amount of Platelet-factor 4 (PF4). This is normally one of the most abundant alpha-granule proteins, and its severe depletion in SRGN-/- platelets led us to investigate the trafficking of PF4 in SRGN-/- MKs. We began by characterizing PF4 retention and release from MKs in vitro and found that immature SRGN-/- MKs release most of the PF4 they produce into the media. This leads to a blunting of MK development in SRGN-/- cultures, where MKs were smaller, had lower ploidy, and did not express MK maturation markers. These findings were recapitulated when wild-type MKs were treated with surfen, an inhibitor of glycosaminoglycan electrostatic interactions. Deletion of SRGN in mice led to the accumulation of PF4, MIP-1, IL-1β, and TNF-α in the bone marrow interstitial fluid and an immature MK population that was smaller in size and had lower ploidy values but was not fewer in number. SRGN-/- mice had lower platelet counts. SRGN-/- mice had reduced numbers of long and short-term hematopoietic stem cells and MPP4s, as well as less laminin in the bone marrow. These findings demonstrate that MKs maintain a balance of PF4 between their alpha-granules and the extracellular space, which is an active process that influences the development of proximal MK progenitors. This regulation depends on SRGN for the retention of PF4. Additionally, we have shown that SRGN is an important factor in maintaining the bone marrow microenvironment’s homeostasis. This is likely through concentrating or transferring growth factors and cytokines within specific niches for cell development.
Digital Object Identifier (DOI)
This work was supported by the NIH/NHLBI (HL150818)
Lykins, Joshua, "The Role of Serglycin in Megakaryocyte Biology and Bone Marrow Niches" (2024). Theses and Dissertations--Molecular and Cellular Biochemistry. 71.
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