3. Optimal TGF-β PMO inhibitors in human Lin-CD34+ CD45+ HSC

TGF-β is a family of multifunctional peptide cytokines with the capacity to regulate proliferation, differentiation, adhesion, migration, and other functions in many cell types. TGF-β receptors are found on most cells, and their signal transduction positively and negatively regulates many other growth factors. Secreted TGF-β is cleaved into a latency-associated peptide (LAP) and a mature TGF-β1 protein. TGF-β is latent in the form of a TGF-β1 homodimer, a LAP homodimer, and a latent TGF-β1-binding protein (LTBP). However, TGF-β1 homodimer can be active, and the mature protein may also form heterodimers with other TGF-β family members.

The HSC is pluripotent immature cell that can generate daughter cells committed to all nine types of mature blood cells, including trillions of white blood cells, red blood cells, and platelets. HSCs are found in the bone marrow and also circulate in the peripheral blood. HSC possesses two key properties: (1) the ability to self-renew (generating HSC replicates) and (2) the ability to generate daughter cells that differentiate into fully functional blood cells (namely, asymmetrical HSC division in which one daughter cell remains a HSC and the other daughter cells are destined to mature).

When the most primitive HSCs self-replicate, they produce daughter cells with a long (possibly unlimited) clonal life span. When HSC replication leads to differentiation divisions, they lose their multi-lineage potential and the corresponding lineage commitment accompanied by a progressive reduction in clonal life span. Previous studies have shown that ex vivo proliferation of HSC favors differentiation divisions at the expense of self-replication, resulting in a complete loss of HSC.
