Jonathan N Thon

Jonathan N Thon
STRM.BIO

PhD

About

72
Publications
25,006
Reads
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2,715
Citations
Citations since 2016
12 Research Items
1849 Citations
2016201720182019202020212022050100150200250
2016201720182019202020212022050100150200250
2016201720182019202020212022050100150200250
2016201720182019202020212022050100150200250
Introduction
Prior to founding Platelet BioGenesis, Jonathan was an Assistant Professor at Brigham and Women’s Hospital and Harvard Medical School, where he retains an academic affiliation. His research focuses on developing bio-mimetic microfluidic platforms for cell culture and functional platelet production.
Additional affiliations
January 2020 - present
STRM.BIO
Position
  • Founder and CEO
August 2017 - December 2019
Platelet Biogenesis
Platelet Biogenesis
Position
  • CEO/CSO, Co-Founder
August 2017 - July 2019
Brigham and Women's Hospital
Position
  • Lecturer
Description
  • Entrepreneur-in-residence, instructor. Help inventors at Harvard and associated institutions translate cutting-edge technology through entrepreneurship.
Education
September 2013 - November 2013
Harvard Medical School
Field of study
  • Healthcare Innovation and Commercialization
September 2012 - October 2012
Harvard Medical School
Field of study
  • Design and Conduct of Clinical Trials
June 2011 - June 2011
Marine Biology Laboratory
Field of study
  • Analytical and Quantitative Light Microscopy

Publications

Publications (72)
Article
The production of in vitro–derived platelets has great potential for transfusion medicine. Here, we build on our experience in the forward programming (FoP) of human pluripotent stem cells (hPSCs) to megakaryocytes (MKs) and address several aspects of the complex challenges to bring this technology to the bedside. We first identify clinical-grade h...
Article
Full-text available
Antisense oligonucleotides (ASOs) are DNA-based, disease-modifying drugs. Clinical trials with 2'-O-methoxyethyl (2’MOE) ASOs have reported dose- and sequencespecific lowering of platelet counts according to two phenotypes. Phenotype 1 is a moderate (but not clinically severe) drop in platelet count. Phenotype 2 is rare, severe thrombocytopenia. Th...
Article
Introduction: There is a growing shortage of platelets, the principal blood cells responsible for clot formation and blood vessel repair at sites of active bleeding. Platelet BioGenesis (PBG) is developing a commercial-scale, donor-free platelet (PLT+) production process using a cGMP-grade human induced pluripotent stem cell line (hiPSC) to address...
Article
In addition to their primary roles in hemostasis and thrombosis, platelets participate in many other physiological and pathological processes, including, but not limited to inflammation, wound healing, tumor metastasis, and angiogenesis. Among their most interesting properties is the large number of bioactive proteins stored in their α-granules, th...
Article
Introduction Antisense oligonucleotides (ASOs) are a new class of single-stranded DNA based drugs that hold great therapeutic promise for their disease modifying potential in a wide range of genetic diseases. Preclinical toxicology studies in monkeys, as well as late stage clinical trials in humans, have upon repeated dosing, reported events of ASO...
Article
Full-text available
The growth factor receptor Kit is involved in hematopoietic and nonhematopoietic development. Mice bearing Kit defects lack mast cells; however, strains bearing different Kit alleles exhibit diverse phenotypes. Herein, we investigated factors underlying differential sensitivity to IgG-mediated arthritis in 2 mast cell-deficient murine lines: KitWsh...
Article
Translating basic research discoveries through entrepreneurship must be scientist driven and institutionally supported to be successful (not the other way around). Here, we describe why scientists should engage in entrepreneurship, where institutional support for scientist-founders falls short, and how these challenges can be overcome.
Article
Full-text available
Platelets, responsible for clot formation and blood vessel repair, are produced by megakaryocytes in the bone marrow. Platelets are critical for hemostasis and wound healing, and are often provided following surgery, chemotherapy, and major trauma. Despite their importance, platelets today are derived exclusively from human volunteer donors. They h...
Article
Full-text available
Lysyl oxidase (LOX) is overexpressed in various pathologies associated with thrombosis, such as arterial stenosis and myeloproliferative neoplasms (MPNs). LOX is elevated in the megakaryocytic lineage of mouse models of MPNs and in patients with MPNs. To gain insight into the role of LOX in thrombosis and platelet function without compounding the i...
Article
Full-text available
We have now examined the erythroid phenotype in this zebrafish strain carrying a ZFN genomic knockout of piezo1. Genotyping was performed as previously described. In contrast to the anemic phenotype observed in zebrafish subjected to morpholino knockdown of piezo, the genomic ZFN knockout of piezo1 did not segregate either with anemia in the 3-dpf...
Article
The production of laboratory-generated human platelets is necessary to meet present and future transfusion needs. This manuscript will identify and define the major roadblocks that must be overcome to make human platelet production possible for clinical use, and propose solutions necessary to accelerate development of laboratory-generated human pla...
Article
An entrepreneurial movement within science strives to invert the classical trajectory of academic research careers by positioning trainees at the apex of burgeoning industries. Young scientists today have nothing to lose and everything to gain by pursuing this ‘third road’, and academic institutes and established companies only stand to benefit fro...
Article
Full-text available
Bone marrow megakaryocytes produce platelets by extending long cytoplasmic protrusions, designated proplatelets, into sinusoidal blood vessels. While microtubules are known to regulate platelet production, the underlying mechanism of proplatelet elongation has yet to be resolved. Here we report that proplatelet formation is a process that can be di...
Article
Full-text available
Human induced pluripotent stem cells (iPSCs) provide a potentially replenishable source for the production of transfusable platelets. Here, we describe a method to generate megakaryocytes (MKs) and functional platelets from iPSCs in a scalable manner under serum/ feeder-free conditions. The method also permits the cryopreservation of MK progenitors...
Article
Although tyrosine phosphorylation of extracellular proteins has been reported to occur extensively in vivo, no secreted protein tyrosine kinase has been identified. As a result, investigation of the potential role of extracellular tyrosine phosphorylation in physiological and pathological tissue regulation has not been possible. Here, we show that...
Article
Key Points We have developed a biomimetic microfluidic platelet bioreactor that recapitulates bone marrow and blood vessel microenvironments. Application of shear stress in this bioreactor triggers physiological proplatelet production, and platelet release.
Article
Full-text available
In this issue of Blood, Niswander et al answer the questions: (1) Does stromal cell-derived factor 1 (SDF-1) direct megakaryocyte spatial distribution in the bone marrow? and (2) What effect does local SDF-1 concentration have on platelet output?(1) If Jose Arcadio Buendia in One Hundred Years of Solitude(2) had followed SDF-1, as megakaryocytes do...
Article
Platelets are essential for haemostasis, and thrombocytopenia (platelet counts <150 × 10(9) /l) is a major clinical problem encountered across a number of conditions, including immune thrombocytopenic purpura, myelodysplastic syndromes, chemotherapy, aplastic anaemia, human immunodeficiency virus infection, complications during pregnancy and delive...
Article
We used exome sequencing to identify mutations in sideroflexin 4 (SFXN4) in two children with mitochondrial disease (the more severe case also presented with macrocytic anemia). SFXN4 is an uncharacterized mitochondrial protein that localizes to the mitochondrial inner membrane. sfxn4 knockdown in zebrafish recapitulated the mitochondrial respirato...
Article
Animating complex biological processes contextualizes them within their underlying physiology, identifies gaps in our mechanistic understanding, affirms the importance of continued research, and provides a bridge between academic scientists and the general public. Here, two videos illustrate the clinical value of and translate state-of-the-art rese...
Article
Full-text available
During thrombopoiesis, megakaroycytes undergo extensive cytoskeletal remodeling to form proplatelet extensions that eventually produce mature platelets. Proplatelet formation is a tightly orchestrated process that depends on dynamic regulation of both tubulin reorganization and Rho-associated, coiled-coil containing protein kinase/RhoA activity. A...
Article
Full-text available
Wnt signaling is involved in numerous aspects of vertebrate development and homeostasis, including the formation and function of blood cells. Here, we show that canonical and non-canonical Wnt signaling pathways are present and functional in megakaryocytes (MKs), with several Wnt effectors displaying MK-restricted expression. Using the CHRF288-11 c...
Article
79 Megaloblastic anemias are characterized by impaired DNA metabolism, often due to deficiencies in vitamin B12 or folate. Genes underlying hereditary forms of megaloblastic anemia not caused by vitamin B12 or folate deficiencies, however, remain largely unknown. Here we characterize a genetic deficiency in a patient with infantile-onset megaloblas...
Article
Full-text available
We recently identified 68 genomic loci where common sequence variants are associated with platelet count and volume. Platelets are formed in the bone marrow by megakaryocytes, which are derived from hematopoietic stem cells by a process mainly controlled by transcription factors. The homeobox transcription factor MEIS1 is uniquely transcribed in me...
Article
Full-text available
Platelets are anucleate, discoid cells, roughly 2-3 μm in diameter that function primarily as regulators of hemostasis, but also play secondary roles in angiogensis and innate immunity. Although human adults contain nearly one trillion platelets in circulation that are turned over every 8-10 days, our understanding of the mechanisms involved in pla...
Article
Full-text available
Human and murine platelets (PLTs) variably express toll-like receptors (TLRs), which link the innate and adaptive immune responses during infectious inflammation and atherosclerotic vascular disease. In this paper, we show that the TLR9 transcript is specifically up-regulated during pro-PLT production and is distributed to a novel electron-dense tu...
Article
Full-text available
Serum response factor and its transcriptional cofactor MKL1 are critical for megakaryocyte maturation and platelet formation. We show that MKL2, a homologue of MKL1, is expressed in megakaryocytes and plays a role in megakaryocyte maturation. Using a megakaryocyte-specific Mkl2 knockout (KO) mouse on the conventional Mkl1 KO background to produce d...
Article
Full-text available
Proplatelet production represents a terminal stage of megakaryocyte development during which long, branching processes composed of platelet-sized swellings are extended and released into the surrounding culture. Whereas the cytoskeletal mechanics driving these transformations have been the focus of many studies, significant limitations in our abili...
Article
Full-text available
Platelet (PLT) production represents the final stage of megakaryocyte (MK) development. During differentiation, bone marrow MKs extend and release long, branched proPLTs into sinusoidal blood vessels, which undergo repeated abscissions to yield circulating PLTs. Circular-prePLTs are dynamic intermediate structures in this sequence that have the cap...
Article
Full-text available
Megakaryocytes release large preplatelet intermediates into the sinusoidal blood vessels. Preplatelets convert into barbell-shaped proplatelets in vitro to undergo repeated abscissions that yield circulating platelets. These observations predict the presence of circular-preplatelets and barbell-proplatelets in blood, and two fundamental questions i...
Article
Driven by the application of immunofluorescence (IF) microscopy and modern molecular biology approaches to cytoskeletal manipulation, the last 5 years have yielded considerable progress to our understanding of the molecular mechanisms governing megakaryocyte development and platelet biogenesis. Such studies have visualized endomitotic spindle dynam...
Article
4821 Megakaryocytes (MKs) release large PLT-like intermediates called prePLTs into sinusoidal blood vessels. PrePLTs will convert into barbell-shaped proPLTs in vitro to undergo repeated abscissions that yield individual circulating PLTs. These observations predict the presence of circular-prePLTs and barbell-proPLTs in human blood and highlight tw...
Article
2336 Background The transcriptional cofactors, MKL1 and MKL2, are members of the myocardin related factor family, which bind and activate the transcription factor Serum Response Factor (SRF) (Cen et al J Cell Biochem, 2004). Megakaryocytes, large, highly polyploid myeloid cells give rise to platelets, which promote blood clotting in response to ti...
Article
366 Human and murine platelets (PLTs) variably express toll-like receptors (TLRs), which link the innate and adaptive immune responses during infectious inflammation and atherosclerotic vascular disease. This is perhaps best exemplified by the observation that severe thrombocytopenia is associated with sepsis. While recent phenotypic and functional...
Article
Full-text available
Megakaryocytes generate platelets by remodeling their cytoplasm first into proplatelets and then into preplatelets, which undergo fission to generate platelets. Although the functions of microtubules and actin during platelet biogenesis have been defined, the role of the spectrin cytoskeleton is unknown. We investigated the function of the spectrin...
Data
Full-text available
Effects of different cytokines and growth factors on MK differentiation and expansion from blast cells.
Data
Characterization of MKs generated from hESCs.
Data
Characterizations of hESC-PLTs generated under OP9 cell co-culture condition.
Data
Full-text available
hESC-platelets adhere to collagen coated surfaces under static conditions in an α2β1 integrin-dependent manner.
Data
Full-text available
Adhesion of hESC-PLTs on bovine serum albumin (BSA) surface.
Data
Full-text available
hESC-PLTs generated under feeder and serum-free condition spread on fibrinogen or vWF surface.
Data
Full-text available
Development of hematopoietic colony forming-unit-megakaryocyte (CFU-MK) from hemangioblasts/blast cells derived from three human embryonic stem cell (hESC) lines.
Data
Flow cytometry analyses of hESC-PLTs generated under serum- and feeder-free conditions.
Data
Full-text available
Functional characterization of hESC-PLTs generated under OP9 cell co-culture condition.
Data
Full-text available
Kinetics of mouse platelet thrombus formation following laser-induced vascular injury in vivo.
Data
Human blood platelets incorporate into the developing mouse platelet thrombus in an αIIbβ3-dependent manner, at the site of laser-induced arteriolar injury in living mice. Dylight 649-labeled anti-mouse CD42 (0.05 μg/g body weight) was infused to monitor a mouse platelet thrombus. Calcein AM-labeled human blood platelets, 50-100 μl (5-10 × 105 plat...
Data
hESC-PLTs incorporate into the developing mouse platelet thrombus in an αIIbβ3-dependent manner, at the site of laser-induced arteriolar injury in living mice. Dylight 649-labeled anti-mouse CD42 (0.05 μg/g body weight) was infused to monitor a mouse platelet thrombus. Calcein AM-labeled hESC-derived platelets, 50-100 μl (5-10 × 105 platelets), wer...
Data
Human blood platelets incorporate into the developing mouse platelet thrombus in an αIIbβ3-dependent manner, at the site of laser-induced arteriolar injury in living mice. Dylight 649-labeled anti-mouse CD42 (0.05 μg/g body weight) was infused to monitor a mouse platelet thrombus. Calcein AM-labeled human blood platelets, 50-100 μl (5-10 × 105 plat...
Data
hESC-PLTs incorporate into the developing mouse platelet thrombus in an αIIbβ3-dependent manner, at the site of laser-induced arteriolar injury in living mice. Dylight 649-labeled anti-mouse CD42 (0.05 μg/g body weight) was infused to monitor a mouse platelet thrombus. Calcein AM-labeled hESC-derived platelets, 50-100 μl (5-10 × 105 platelets), wer...
Article
Full-text available
Platelets play an essential role in hemostasis and atherothrombosis. Owing to their short storage time, there is constant demand for this life-saving blood component. In this study, we report that it is feasible to generate functional megakaryocytes and platelets from human embryonic stem cells (hESCs) on a large scale. Differential-interference co...
Article
Full-text available
Megakaryocytes generate platelets by remodeling their cytoplasm into long proplatelet extensions, which serve as assembly lines for platelet production. Although the mechanics of proplatelet elongation have been studied, the terminal steps of proplatelet maturation and platelet release remain poorly understood. To elucidate this process, released p...
Article
Thrombocytopenia is the underlying cause of a number of major clinical conditions and genetic disorders worldwide. While therapeutic agents that bind and stimulate the thrombopoietin receptor are currently available, the development of drugs that directly stimulate megakaryocytes to generate platelets has lagged behind. To improve the management of...
Article
4590 Megakaryocytes generate platelets by remodeling their cytoplasm into long proplatelet extensions from which platelets release. While the mechanics of proplatelet elongation have been studied, the terminal steps of platelet production remain poorly understood. To understand the mechanics of platelet release, we developed a novel gradient sedime...
Article
Full-text available
The spontaneous mouse mutation "thrombocytopenia and cardiomyopathy" (trac) causes macrothrombocytopenia, prolonged bleeding times, anemia, leukopenia, infertility, cardiomyopathy, and shortened life span. Homozygotes show a 20-fold decrease in platelet numbers and a 3-fold increase in platelet size with structural alterations and functional impair...
Article
The term platelet storage lesion (PSL) describes the structural and biochemical changes in platelets (PLTs) during storage. These are typified by alterations of morphologic features and PLT metabolism leading to reduced functionality and hence reduced viability for transfusion. While the manifestations of the storage lesion are well characterized,...
Article
Platelet storage and availability for the purposes of transfusion are currently restricted by a markedly short shelf life of 5 to 7 days owing to an increased risk of bacterial growth and storage-related deterioration called the platelet storage lesion. Because most bacteria grow to confluence within 5 days during storage at room temperature, there...
Article
Proteomics methods may be used to analyze changes occurring in stored blood products. These data sets can identify processes leading to storage-associated losses of blood component quality such as the platelet (PLT) storage lesion (PSL). The optimal strategy to perform such analyses to obtain the most informative data sets, including which proteomi...
Article
Platelet (PLT) products have a short shelf life (5 days) owing in part to the deterioration of the quality of PLTs stored at 22 degrees C. This creates significant inventory challenges, and blood banks may suffer shortages and high wastage as a result. The precise biochemical pathways involved in the PLT storage lesion are unknown and must be under...
Article
Platelet transfusion is a standard live-saving medical procedure for patients with platelet-deficient diseases like leukemia. Platelets have a limited shelf-life of 5–7 days for transfusion purposes. This is in part due to a storage-related deterioration typified by altered morphology features and platelet metabolism as well as increased platelet a...