An epigenetically distinct HSC subset supports thymic reconstitution.

Area of Science:

• Immunology
• Stem Cell Biology
• Hematopoiesis

Background:

• Hematopoietic stem cells (HSCs) are crucial for immune system restoration after allogeneic Hematopoietic Cell Transplantation (allo-HCT).
• The Kit^lo subset of HSCs shows promise for multipotent precursor activity.
• The T-cell lineage potential of Kit^lo HSCs remains incompletely understood.

Purpose of the Study:

• To investigate the thymic reconstituting and T-cell potential of Kit^lo HSCs.
• To explore the role of Kit^lo HSCs in age-associated immune decline and T-cell recovery.
• To elucidate the molecular mechanisms, including transcription factor activity, governing Kit^lo HSC lymphoid potential.

Main Methods:

• Utilized a preclinical allo-HCT model to assess thymic and T-cell recovery.
• Analyzed the frequency and function of Kit^lo HSCs in aged versus young mice.
• Performed chromatin profiling to identify key transcription factors (TFs) and gene regulatory networks.
• Genetically manipulated Zbtb1 expression in HSC subsets to evaluate its impact on T-cell potential in vitro and in vivo.

Main Results:

• Kit^lo HSCs demonstrated superior thymic recovery and T-cell reconstitution post-allo-HCT, leading to enhanced T-cell responses.
• These HSCs mitigated age-related thymic alterations, improving T-cell recovery in middle-aged hosts.
• The frequency of Kit^lo HSCs decreased with age, correlating with reduced T-lymphopoietic potential.
• Chromatin profiling revealed heightened activity of lymphoid-specifying TFs, notably Zbtb1, in Kit^lo HSCs.
• Zbtb1 deletion impaired T-cell potential, while its reintroduction into Kit^hi HSCs restored it.
• An analogous human Kit^lo HSC subset with enhanced lymphoid potential was identified.

Conclusions:

• Kit^lo HSCs possess a distinct epigenetic program that enhances lymphoid potential and T-cell reconstitution.
• The age-related decline in Kit^lo HSC frequency contributes to impaired T-cell immunity in aged individuals.
• Zbtb1 is a critical regulator of HSC lymphoid lineage specification and T-cell potential.
• Targeting Kit^lo HSCs and their associated epigenetic regulators offers a promising strategy for improving immune reconstitution after allo-HCT.