| Autor: |
Macias, Alejandra, Cortes, Mauricio, An, Na, Li, Na, Fulton, Timothy, Simpson, Allison, Miller, Samuel, Sun, Sunny, Fu, Doris, Garcia, Juan, Medicherla, Satya, Steelman, Scott, Thorarensen, Atli, Goddeeris, Matthew, Krishnamoorthy, Sriram |
| Zdroj: |
Blood; November 2023, Vol. 142 Issue: 1, Number 1 Supplement 1 p5580-5580, 1p |
| Abstrakt: |
Hematopoietic stem cells undergo a multi-step differentiation program through several precursor stages to give rise to megakaryocytes (Mk), which ultimately release platelets. Thrombocytopenia can manifest in various clinical settings and can adversely affect a patient's quality of life through easy bruising and risk of bleeding. An example is chemotherapy-induced thrombocytopenia (CIT) which occurs when myelosuppressive chemotherapy is given, especially with certain agents such as platinum analogs and cyclophosphamide. We used a single-cell RNA-sequencing approach to study the differentiation of hematopoietic stem cells to Mk progenitors (MkP) and delineated the trajectory that defines the transition of cells to the megakaryocytic lineage. Using our proprietary platform which pairs new approaches in computation and machine learning in drug discovery, we predicted small molecule interventions that could modulate the hematopoietic lineage direction to increase the differentiation towards MkP and subsequent increases in platelet counts. Using an in vitro5-day CD34-based Mk differentiation assay we demonstrated that some of our predicted interventions increased generation of MkP from stem cells. Analysis of early MkP (CD34-CD235a-CD71+CD41b+CD42b-) and late MkP (CD34-CD235a-CD71-CD41b+CD42b+) by flow cytometry elucidated differential mechanisms of action such as induction of early or late MKP or both. We performed an 8-day study in healthy mice, which revealed that a selected set of compounds increased MkPs in vivo, consistent with our predicted cell behavior and in vitrofindings. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
|
