OC 18.2 - Differentiation route determines the functional outputs of adult megakaryopoiesis

Sunday, June 23, 2024

09:45 – 10:00 ICT

Room: 211 A-D

Presenting Author(s)

Yueying Li, MD

Professor
Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation
Beijing, Beijing, China (People's Republic)

Co-Author(s)

JL

Jing-jing Li

Doctoral Student
Chinese Academy of Medical Sciences & Peking Union Medical College
Tianjin, Tianjin, China (People's Republic)
Jingkun Liu

PhD student
Beijing Institute of Genomics, Chinese Academy of Sciences (CAS)
Beijing, Beijing, China (People's Republic)
YL

Yunqian Evelyn Li

PhD student
Shanghai Institute of Biochemistry and Cell Biology, CAS
Shanghai, Shanghai, China (People's Republic)
LC

Lin Veronica Chen

PhD student
Shanghai Institute of Biochemistry and Cell Biology, CAS
Shanghai, Shanghai, China (People's Republic)
HC

Hui Cheng

Professor
Chinese Academy of Medical Sciences & Peking Union Medical College
Tianjin, Tianjin, China (People's Republic)
TC

Tao Cheng

Professor
Chinese Academy of Medical Sciences & Peking Union Medical College
Tianjin, Tianjin, China (People's Republic)
QW

Qian-fei Wang

Principle Investigator
Beijing Institute of Genomics, Chinese Academy of Sciences (CAS)
Beijing, Beijing, China (People's Republic)
BZ

Bo O. Zhou

Principle Investigator
Shanghai Institute of Biochemistry and Cell Biology, CAS
Shanghai, Shanghai, China (People's Republic)

Background: Emerging evidence has supported a direct differentiation route from hematopoietic stem cells to megakaryocytes, bypassing the stepwise hematopoietic hierarchy. This raises a fundamental question of the physiological importance of two alternative differentiation routes for megakaryopoiesis. Single-cell RNA sequencing (scRNA-seq) has decoded the cellular heterogeneity of megakaryocytes and confirmed the existence of platelet-producing, niche-supporting and immune MK subpopulations in both human and mouse.

Aims: To investigate the biological significance of the distinct differentiation routes and diverse functions of megakaryocytes under both homeostatic and stress conditions.

Methods: We developed fate-mapping systems (Cd48dre; R26rox-tdTomato mice model) to distinguish the direct and stepwise differentiation routes, comparing their quantitative and functional outputs. Further, we performed single-cell RNA-sequencing, in vitro and in vivo assays of the fate-mapped MKs. 5-fluorouracil (5-FU) induced myeloablation and lipopolysaccharide (LPS) induced inflammation was performed on Cd48dre;R26rox-tdTomato mice.

Results: We found that megakaryocytes were produced through the two routes with comparable kinetics and quantity under homeostasis. Single-cell RNA-sequencing of the fate-mapped megakaryocytes revealed that the direct and stepwise routes contributed to the niche-supporting and immune megakaryocytes respectively, but contributed to the platelet-producing megakaryocytes together. Consistent with this, megakaryocytes generated through different routes displayed different activities in vitro and in vivo. 5-FU induced myeloablation preferentially enhanced megakaryopoiesis through the direct route, whereas LPS induced inflammation preferentially enhanced megakaryopoiesis through the stepwise route.

Conclusion(s): In summary, our work links the differentiation route to the cellular heterogeneity of adult megakaryocytes. Alternative differentiation routes result in variable combinations of functionally distinct megakaryocyte subpopulations poised for different physiological demands.