Highly efficient platelet generation in lung vasculature reproduced by microfluidics

Zhao, Xiaojuan; Alibhai, Dominic; Walsh, Tony G.; Tarassova, Nathalie; Englert, Maximilian; Birol, Semra Zuhal; Li, Yong; Williams, Christopher; Neal, Chris; Burkard, Philipp; Cross, Stephen; Aitken, Elizabeth; Waller, Amie K.; Ballester-Beltrán, José; Gunning, Peter W.; Hardeman, Edna C.; Agbani, Ejaife O.; Nieswandt, Bernhard; Hers, Ingeborg; Ghevaert, Cédric; Poole, Alastair W.

doi:10.1038/s41467-023-39598-9

Cited by 16 publications

(14 citation statements)

References 53 publications

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“…We utilized a model for studying the biology of released human platelets that we had previously described (Figure 6A). This model recapitulates the pulmonary release of platelets from megakaryocytes 44 and where the released platelets closely resemble donor-derived platelets 25 . We found that both unmodified and uPA-exposed MK released a similar number of platelets per infused megakaryocyte, time to maximal platelet release, and platelet survival at 24 hours (Figure 6B).…”

Section: Resultsmentioning

confidence: 68%

Packaging of supplemented urokinase into naked alpha-granules ofin vitro-grown megakaryocytes for targeted therapeutic delivery

Poncz,

Zaitsev,

Ahn

et al. 2023

Preprint

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Our prior finding that uPA endogenously expressed and stored in the platelets of transgenic mice prevented thrombus formation without causing bleeding, prompted us to develop a potentially clinically relevant means of generating anti-thrombotic human plateletsin vitrofrom CD34+hematopoietic cell-derived megakaryocytes. CD34+-megakaryocytes internalize and store in α-granules single-chain uPA (scuPA) and a uPA variant modified to be plasmin-resistant, but thrombin-activatable, (uPAT). Both uPAs co-localized with internalized factor V (FV), fibrinogen and plasminogen, low-density lipoprotein receptor-related protein 1 (LRP1), and interferon-induced transmembrane protein 3 (IFITM3), but not with endogenous von Willebrand factor (VWF). Endocytosis of uPA by CD34+-\megakaryocytes was mediated in part via LRP1 and αIIbβ3. scuPA-containing megakaryocytes degraded endocytosed intragranular FV, but not endogenous VWF, in the presence of internalized plasminogen, whereas uPAT-megakaryocytes did not significantly degrade either protein. We used a carotid-artery injury model in NOD-scid IL2rγnull (NSG) mice homozygous for VWFR1326H(a mutation switching binding VWF specificity from mouse to human glycoprotein IbmlIX) to test whether platelets derived from scuPA-MKs or uPAT-Mks would prevent thrombus formation. NSG/VWFR1326Hmice exhibited a lower thrombotic burden after carotid artery injury compared to NSG mice unless infused with human platelets or MKs, whereas intravenous injection of either uPA-containing megakaryocytes into NSG/VWFR1326Hgenerated sufficient uPA-containing human platelets to lyse nascent thrombi. These studies suggest the potential to deliver uPA or potentially other ectopic proteins within platelet α-granules fromin vitro-generated megakaryocytes.Key pointsUnlike platelets, in vitro-grown megakaryocytes can store exogenous uPA in its α-granules.uPA uptake involves LRP1 and αIIbβ3 receptors and is functionally available from activated platelets.

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Section: Resultsmentioning

confidence: 68%

Packaging of supplemented urokinase into naked alpha-granules ofin vitro-grown megakaryocytes for targeted therapeutic delivery

Poncz,

Zaitsev,

Ahn

et al. 2023

Preprint

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“…Already published morphometry data documented a presence of 14-65 MKs/cm 2 in the lung (which were denser in the central and right upper lobes) [65]. However, MKs are almost 10 times more concentrated in the pulmonary artery than the aorta [66].…”

Section: Development Of Plateletsmentioning

confidence: 97%

Platelet-Rich Plasma in Dermatology: New Insights on the Cellular Mechanism of Skin Repair and Regeneration

Manole,

Soare,

Ceafalan

et al. 2023

Life

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The skin’s recognised functions may undergo physiological alterations due to ageing, manifesting as varying degrees of facial wrinkles, diminished tautness, density, and volume. Additionally, these functions can be disrupted (patho)physiologically through various physical and chemical injuries, including surgical trauma, accidents, or chronic conditions like ulcers associated with diabetes mellitus, venous insufficiency, or obesity. Advancements in therapeutic interventions that boost the skin’s innate regenerative abilities could significantly enhance patient care protocols. The application of Platelet-Rich Plasma (PRP) is widely recognized for its aesthetic and functional benefits to the skin. Yet, the endorsement of PRP’s advantages often borders on the dogmatic, with its efficacy commonly ascribed solely to the activation of fibroblasts by the factors contained within platelet granules. PRP therapy is a cornerstone of regenerative medicine which involves the autologous delivery of conditioned plasma enriched by platelets. This is achieved by centrifugation, removing erythrocytes while retaining platelets and their granules. Despite its widespread use, the precise sequences of cellular activation, the specific cellular players, and the molecular machinery that drive PRP-facilitated healing are still enigmatic. There is still a paucity of definitive and robust studies elucidating these mechanisms. In recent years, telocytes (TCs)—a unique dermal cell population—have shown promising potential for tissue regeneration in various organs, including the dermis. TCs’ participation in neo-angiogenesis, akin to that attributed to PRP, and their role in tissue remodelling and repair processes within the interstitia of several organs (including the dermis), offer intriguing insights. Their potential to contribute to, or possibly orchestrate, the skin regeneration process following PRP treatment has elicited considerable interest. Therefore, pursuing a comprehensive understanding of the cellular and molecular mechanisms at work, particularly those involving TCs, their temporal involvement in structural recovery following injury, and the interconnected biological events in skin wound healing and regeneration represents a compelling field of study.

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“…Not only are they associated with hemostasis and thrombosis, but they are also involved in other physiological and pathological processes. 106,107 The bone marrow has been thought to be the site of MK maturation and platelet production, but recently, it has been shown that the lungs are the primary site of terminal platelet production, accounting for approximately 50% of total platelet production. 108 Platelets are an important type of immune cell.…”

Section: Plateletsmentioning

confidence: 99%

Lung regeneration: diverse cell types and the therapeutic potential

Chen,

Li,

et al. 2024

MedComm

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Lung tissue has a certain regenerative ability and triggers repair procedures after injury. Under controllable conditions, lung tissue can restore normal structure and function. Disruptions in this process can lead to respiratory system failure and even death, causing substantial medical burden. The main types of respiratory diseases are chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute respiratory distress syndrome (ARDS). Multiple cells, such as lung epithelial cells, endothelial cells, fibroblasts, and immune cells, are involved in regulating the repair process after lung injury. Although the mechanism that regulates the process of lung repair has not been fully elucidated, clinical trials targeting different cells and signaling pathways have achieved some therapeutic effects in different respiratory diseases. In this review, we provide an overview of the cell type involved in the process of lung regeneration and repair, research models, and summarize molecular mechanisms involved in the regulation of lung regeneration and fibrosis. Moreover, we discuss the current clinical trials of stem cell therapy and pharmacological strategies for COPD, IPF, and ARDS treatment. This review provides a reference for further research on the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials.

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Highly efficient platelet generation in lung vasculature reproduced by microfluidics

Cited by 16 publications

References 53 publications

Packaging of supplemented urokinase into naked alpha-granules ofin vitro-grown megakaryocytes for targeted therapeutic delivery

Packaging of supplemented urokinase into naked alpha-granules ofin vitro-grown megakaryocytes for targeted therapeutic delivery

Platelet-Rich Plasma in Dermatology: New Insights on the Cellular Mechanism of Skin Repair and Regeneration

Lung regeneration: diverse cell types and the therapeutic potential

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