YOKOTA Takafumi ≪Hematology and Oncology≫ “The Satb1 protein directs hematopoietic stem cell differentiation toward lymphoid lineages”

Click to enlarge

PublishImmunity 38:1105-1115 (2013)

Mechanisms for priming hematopoietic stem cells (HSC) to particular lineages remain unknown.
Lymphopoiesis becomes compromised along aging, and previous studies have shown that early stages proximate to HSC are particularly affected.
If key inducers that govern the early lymphoid program could be identified,
their manipulation should be useful for expanding lymphocytes for clinical purposes and it might boost the immune system of immuno-compromised and/or elderly people. A major goal of our study was to find key genes involved in specification of lymphoid fates, and therefore we focused on modulators for chromatin structure that regulate expression and/or function of transcription factors. We performed microarrays comparing HSC and early lymphocyte progenitors and identified Special AT-rich Sequence Binding 1 (Satb1), a global chromatin regulator, as a lymphoid-related gene. Real-time RT-PCR confirmed that Satb1 expression increases along early lymphoid differentiation whereas it markedly decreases in myeloid progenitors. HSC from Satb1-null mouse bone marrow failed to reconstitute T-lymphopoiesis in wild-type recipients, indicating the essential role of Satb1 in lymphopoiesis. Furthermore, Satb1 over-expression in bone marrow HSC robustly promoted their differentiation primarily toward lymphocytes in culture. Satb1 over-expression effectively induced lymphocyte growth even from embryonic stem cells in OP9 co-culture. Microarray analyses comparing Satb1- and Mock-transduced HSC demonstrated that expression of various genes involved in lineage fate decisions was affected by Satb1 over-expression. Satb1 expression was significantly reduced in aged HSC that are compromised in lymphopoietic potential, and forced Satb1 expression partly restored that potential. In summary, Satb1 governs the initiating process important for replenishing the lymphoid lineage. Such activity in generating lymphoid cells may be of clinical significance and useful to overcome immuno-senescence.