Project Grant R01HL172940

CHARACTERIZATION OF MULTILINEAGE DEFINITIVE HEMATOPOIETIC PROGENITORS FROM HUMAN PLURIPOTENT STEM CELLS - PROJECT SUMMARY / ABSTRACT HEMATOPOIETIC STEM CELLS (HSCS) ARE STEM CELLS THAT REPLENISH THE ENTIRE SUITE OF BLOOD CELLS NEEDED THROUGHOUT ADULT LIFE, AND ARE AN IMPORTANT SOURCE FOR CELL REPLACEMENT THERAPIES AND DISEASE MODELING STUDIES. THE OVERALL GOAL OF OUR RESEARCH IS TO UNDERSTAND HOW TO DERIVE THESE IMPORTANT CELLS, IN A PETRI DISH, FROM HUMAN PLURIPOTENT STEM CELLS (HPSCS). WHILE THE SIGNAL REQUIREMENTS FOR THIS REMAIN UNCLEAR, WE HAVE RECENTLY UNCOVERED A NOVEL DIFFERENTIATION APPROACH, YIELDING CD34+ PROGENITORS THAT HARBOR BOTH TRANSCRIPTIONAL AND FUNCTIONAL PROPERTIES THAT ARE SIMILAR TO NASCENT HSCS. THIS METHODOLOGY EMPLOYS STAGE-SPECIFIC RETINOIC ACID (RA) SIGNALING, AND YIELDS A POPULATION OF CELLS CAPABLE OF HOMING TO RECIPIENT BONE MARROW, AND GIVE RISE TO DIFFERENTIATED PROGENY. WE HYPOTHESIZE THAT THIS POPULATION IS UNIQUE, AND A PRECURSOR TO THE HSC THAT REQUIRES ADDITIONAL SIGNALS DURING ITS SPECIFICATION, TO CONFER SELF-RENEWAL CAPACITY. WE WILL TEST THIS HYPOTHESIS ACROSS 2 SPECIFIC AIMS. IN AIM 1, WE WILL CHARACTERIZE THE TRANSCRIPTIONAL AND SIGNAL DEPENDENCIES FOR THE DEVELOPMENT OF THESE CELLS, AND UNDERSTAND THE ROLE OF DIFFERENTIAL SPLICING IN A CRITICAL TRANSCRIPTION FACTOR. IN AIM 2, WE WILL DEFINE THE TRANSLATIONAL POTENTIAL OF THE LYMPHOID CELLS THAT CAN BE OBTAINED FROM HPSCS, VIA RA-DEPENDENT AND RA-INDEPENDENT MECHANISMS. THE OBJECTIVE OF THESE STUDIES IS TO UNDERSTAND THE DEVELOPMENT AND REGULATION OF HSCS FROM HPSCS, AND WHETHER HSC-INDEPENDENT LYMPHOID CELLS MAY BE A VIABLE ALTERNATIVE SOURCE FOR ADOPTIVE IMMUNOTHERAPEUTICS. THIS IS OF FUNDAMENTAL IMPORTANCE TO BOTH BASIC AND TRANSLATIONAL BIOLOGY, AND THE INSIGHTS GENERATED FROM THESE STUDIES WILL HAVE CLINICAL IMPLICATIONS. OUR UNIQUE CELLULAR AND MOLECULAR TOOLS, COMBINED WITH OUR EXPERTISE IN HEMATOPOIESIS, STEM CELL BIOLOGY AND BIOINFORMATICS PUTS US IN AN IDEAL POSITION TO MAKE A SIGNIFICANT IMPACT IN THIS FIELD.