2. Academic Validation
  3. Epigenome editing of human hematopoietic stem cells enables sustained and reversible thrombosis prevention

Epigenome editing of human hematopoietic stem cells enables sustained and reversible thrombosis prevention

  • bioRxiv. 2026 Mar 29:2026.03.27.714536. doi: 10.64898/2026.03.27.714536.
Tianyi Ye 1 2 3 4,  Wanying Xu 1 2 3 4,  Maria N Barrachina 5 6,  Peng Lyu 1 2 3 4,  Mateusz Antoszewski 1 2 3 4,  Lucrezia Della Volpe 1 2 3 4,  Chun-Jie Guo 1 2 3 4,  Andrew J Lee 1 2 3 4,  Madelaine S Theardy 1 2 3 4,  Spencer D Shelton 1 2 3 4,  Lara Wahlster 1 2 3 4,  Alexis Caulier 1 2 3 4,  Luana Messa 1 2 3 4,  Michael Poeschla 1 2 3 4,  Gaurav Agarwal 1 2 3 4,  Ronodeep Mitra 7 8,  Alec A Schmaier 7 8,  Jonathan S Weissman 9 10 11,  Kellie R Machlus 5 6,  Vijay G Sankaran 1 2 3 4 12
Affiliations

Affiliations

  • 1 Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Howard Hughes Medical Institute, Boston, MA 02115, USA.
  • 4 Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  • 5 Vascular Biology Program, Boston Children's Hospital, Boston, MA 02115, USA.
  • 6 Department of Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 7 Cardiovascular Research Center, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
  • 8 Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
  • 9 Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
  • 10 Department of Biology and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA, 02142, USA.
  • 11 David H. Koch Institute for Integrative Cancer Research and Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
  • 12 Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
PMID: 41928991 DOI: 10.64898/2026.03.27.714536
Abstract

Thrombosis remains a major cause of cardiovascular and cerebrovascular diseases, driven in large part by platelet activation and aggregation. Because platelets are continuously produced from hematopoietic stem cells (HSCs), durable reprogramming of HSC output offers a unique opportunity for a one-time antithrombotic intervention. Here, we show that DNA methylation-based epigenome editors delivered transiently as RNA result in stable, heritable gene silencing in primary human HSCs that persists through long-term self-renewal and megakaryocytic differentiation, while remaining reversible through targeted demethylation. Targeting the platelet Integrin β3 (ITGB3), this approach achieves robust, sustained repression and yields platelets with impaired aggregation. Extending this framework to additional genetically-nominated platelet targets establishes HSC epigenome editing as a durable and reversible strategy to modulate thrombotic risk and highlights broader opportunities to engineer hematopoiesis.

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