Spliceosome inhibitor induces human hematopoietic progenitor cell reprogramming toward stemness

Area of Science:

• Stem cell biology
• Hematopoiesis
• Chemical biology

Background:

• Hematopoietic stem cells (HSCs) are crucial for blood formation but are limited in supply, hindering clinical applications.
• Current methods like cell expansion and pluripotent stem cell differentiation have not yielded clinically viable HSCs.
• Generating HSCs via cell reprogramming presents a promising alternative.

Discussion:

• This study demonstrates, for the first time, the chemical reprogramming of human committed hematopoietic progenitors into multipotent progenitors using a spliceosome inhibitor.
• Reprogramming was confirmed using single-cell RNA-sequencing and genetic lineage tracing (exogenous barcodes and endogenous mitochondrial DNA mutations).
• The spliceosome inhibitor induced plasticity, but not full stem cell potential, in differentiated progenitors.

Key Insights:

• Human committed hematopoietic progenitors can be reprogrammed into multipotent progenitors by inhibiting the spliceosome.
• This research validates a two-step strategy for future HSC generation: differentiate HSCs into progenitors, then reprogram progenitors into HSCs.
• The findings advance the understanding of chemical reprogramming and hematopoiesis.

Outlook:

• Further research into the mechanism of spliceosome inhibitor-induced reprogramming is needed.
• This approach could pave the way for generating clinical-grade human HSCs.
• Understanding this process will also illuminate normal and pathological hematopoiesis.