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Megakaryocytes assemble a three-dimensional cage of extracellular matrix that controls their maturation and anchoring to the vascular niche

Claire Masson, Cyril Scandola, Jean-Yves Rinckel, Fabienne Proamer, Emily Janus-Bell, Fareeha Batool, Naël Osmani, Jacky G. Goetz, Léa Mallo, Catherine Léon, Alicia Bornert, Renaud Poincloux, Olivier Destaing, Alma Mansson, Hong Qian, Maxime Lehmann, Anita Eckly

Posted on: 21 February 2025 , updated on: 5 December 2025

Preprint posted on 31 October 2024

Article now published in eLife at http://dx.doi.org/10.7554/eLife.104963

The megakaryocyte: trapped in a cage of its own making

Selected by Simon Cleary

Categories: cell biology, physiology

Updated 5 December 2025 with a postLight by Simon Cleary

This preprint has now been reviewed and published at eLife. The authors have made multiple additions, including a striking demonstration that bone marrow megakaryocytes are attached to their extracellular matrix cages through showing that cages are retained on megakaryocytes isolated from dissociated bone marrow. Movies allow us to better appreciate the 3-dimensional structure of cages. Measurements of nucleated megakaryocyte intravasation into bone marrow sinusoids have been added from mice lacking either Itgb1 or Itgb3 expression in megakaryocytes, indicating redundant roles for these integrins in controlling megakaryocyte intravasation.

These updates are evidence that the eLife model (giving authors freedom to decide how to revise their manuscript without fear of post-review rejection) can still motivate scientists to produce new data in response to reviewer feedback.

Data presented in the preprint had already convinced me that extracellular matrix cages exist and impact megakaryocyte intravasation. I look forward to reading future studies exploring how extracellular matrix cage interactions shape megakaryocyte functions in steady-state conditions and in pathophysiology.

Background

To produce platelets, giant bone marrow-resident megakaryocytes invade blood vessels, releasing protrusions into the bloodstream. Some of these protrusions are particularly large and even drag with them material from massive megakaryocyte nuclei. Fortunately, the pulmonary circulation efficiently fragments this megakaryocyte material into much smaller pieces that eventually become tiny platelets. Still, blood sometimes bypasses the lungs and we would be in constant danger of heart attacks or strokes if an important blood vessel in the heart or brain became blocked by bloodborne megakaryocyte material. One way to prevent megakaryocytes from causing ischemic events would be to control the size of megakaryocyte protrusions entering the bloodstream. In this study, Masson, Scandola and colleagues report the discovery of novel structures controlling megakaryocyte protrusion events: extracellular matrix cages surrounding megakaryocytes.

Key findings

  • Megakaryocytes in the bone marrow are active players in the construction of an extracellular matrix cage around themselves, resembling a watermelon growing into a wire fence!
  • Mice lacking expression of Itgb1 and Itgb3 in their megakaryocytes display larger gaps in these megakaryocyte cages, more large megakaryocyte protrusions entering blood vessels, and low blood platelet counts.
  • Matrix metalloproteinase inhibitor treatment increases the density of cages surrounding megakaryocytes.

Above: Photo of watermelon growing into a wire fence (left, from Reddit) and images of half-megakaryocytes and surrounding ‘cages’ (courtesy and copyright of A. Eckly and C. Masson, UMR_S1255, Strasbourg, France).

Why this work is interesting

  • The cages formed around the megakaryocytes are visually striking and it is easy to imagine how these structures could influence protrusion size.
  • Exactly how platelets are produced remains a hot topic, with several different theories about the relative contribution of proplatelet release in the bone marrow, pulmonary fragmentation, and direct ‘budding’ of individual platelets from megakaryocytes. Effects, and lack of effects, of interventions on platelet counts in this study will be of interest to proponents of each of these platelet production mechanisms.
  • The effects of treatment with batimastat and ilomastat on megakaryocytes may be relevant to adverse or beneficial effects of therapeutics inhibiting matrix metalloproteinases.

Questions I would like to ask the authors about their work

  1. Do the mice lacking Itgb1 and Itgb3 in megakaryocytes show any signs of lung or systemic pathology that might be related to increased release of megakaryocytes into the bloodstream? There is a theory that excessive escape of megakaryocyte material in the systemic circulation causes digital clubbing, but I am not sure whether this can happen in mice.
  2. You mention a possible effect of treatment with MMP inhibitors on platelet clearance, do you have any plans to study this further with platelet lifespan assays? It is intriguing that blood platelet counts remain normal in these mice with denser ‘cages’ surrounding their megakaryocytes.
  3. Did your findings change your thinking about the relative contributions of large protrusions, budding and pulmonary fragmentation to platelet production?

Tags: bone marrow, extracellular matrix, megakaryocytes, platelets

doi: https://doi.org/10.1242/prelights.39683

Read preprint (No Ratings Yet)

Author's response

Anita Eckly and Claire Masson shared

  1. The increased number of circulating megakaryocytes (MKs) in mice lacking Itgb1 and Itgb3 in MKs may lead to vascular obstruction in pulmonary capillaries and provoke an inflammatory response, as MKs can affect immune functions. Under physiological conditions, these mice do not show intracranial bleeding or lung dysfunction (unpublished observations). However, recent studies in our lab reveal that they can develop inflammatory pulmonary issues and intracranial bleeding in a transient middle cerebral artery occlusion (tMCAO) model (Janus-Bell et al., 2024). While this may be linked to the impaired hemostatic functions of β1 and β3 integrins on platelets, the specific contribution of the increased MKs is not known. There is currently no evidence of digital clubbing in DKO Itgb1 and Itgb3 mice.
  2. The impact of MMP inhibitors on megakaryocyte maturation, while keeping platelet counts normal, is an interesting issue. Indeed, one explanation could be a compensatory mechanism that extends the lifespan of circulating platelets, maintaining counts despite impaired MK maturation. We definitely plan to explore this further. Alternatively, it is possible that the remaining functional MKs are more efficient in producing proplatelets, despite their impairment in maturation. Our explant experiments have already provided valuable insights into this area.
  3. Yes, our recent findings, which include insights from this paper as well as advancements in imaging techniques and in vitro 3D bone marrow models, have provided us with a deeper understanding of the roles played by large protrusions, budding, and pulmonary fragmentation in platelet production. Here are the key points:
    Pulmonary Fragmentation: We view this process primarily as pathological, with occurrences noted mainly in conditions such as COVID-19 or in genetically modified mice (mice lacking Itgb1 and Itgb3 or RhoA). As such, it does not appear to play a significant role in normal physiological platelet production.
    Platelet Budding: We rarely observed the process in vivo. Our recent investigations have revealed that bone marrow confinement-mediated high MK intracellular tension is responsible for the formation of the peripheral zone, a unique actin-rich structure. This zone appears to inhibit budding and proplatelet extension in the interstitial space (Guinard et al., Blood Advance, 2024). In addition, our high-resolution 3D FIB-SEM studies have unveiled two distinct structures on the MK surface:
    – The majority seem to lack granules and may be microvesicles, as discussed by Flaumenhaft et al. (Blood, 2009) and Carminita et al. (Circ Res. 2024)
    – A smaller fraction resembles membrane buds that contain granules, as described by Potts et al. (JEM, 2021) and Ellis et al. (Blood, 2023). However, it’s worth noting that these platelet-like buds appear to be rare and are released into the stroma rather than contributing to the pool of circulating platelets.
    Large Protrusions: While our findings acknowledge the existence of alternative mechanisms such as budding and pulmonary fragmentation, they strengthen the view that large protrusions remain the predominant process of platelet formation under normal physiological conditions, reinforcing their importance in our understanding of platelet biology.

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