Variable SATB1 Levels Regulate Hematopoietic Stem Cell Heterogeneity with Distinct Lineage Fate

Publication date: 12 June 2018
Source:Cell Reports, Volume 23, Issue 11
Author(s): Yukiko Doi, Takafumi Yokota, Yusuke Satoh, Daisuke Okuzaki, Masahiro Tokunaga, Tomohiko Ishibashi, Takao Sudo, Tomoaki Ueda, Yasuhiro Shingai, Michiko Ichii, Akira Tanimura, Sachiko Ezoe, Hirohiko Shibayama, Terumi Kohwi-Shigematsu, Junji Takeda, Kenji Oritani, Yuzuru Kanakura
Hematopoietic stem cells (HSCs) comprise a heterogeneous population exhibiting self-renewal and differentiation capabilities; however, the mechanisms involved in maintaining this heterogeneity remain unclear. Here, we show that SATB1 is involved in regulating HSC heterogeneity. Results in conditional Satb1-knockout mice revealed that SATB1 was important for the self-renewal and lymphopoiesis of adult HSCs. Additionally, HSCs from Satb1/Tomato-knockin reporter mice were classified based on SATB1/Tomato intensity, with transplantation experiments revealing stronger differentiation toward the lymphocytic lineage along with high SATB1 levels, whereas SATB1⁻ HSCs followed the myeloid lineage in agreement with genome-wide transcription and cell culture studies. Importantly, SATB1⁻ and SATB1⁺ HSC populations were interconvertible upon transplantation, with SATB1⁺ HSCs showing higher reconstituting and lymphopoietic potentials in primary recipients relative to SATB1⁻ HSCs, whereas both HSCs exhibited equally efficient reconstituted lympho-hematopoiesis in secondary recipients. These results suggest that SATB1 levels regulate the maintenance of HSC multipotency, with variations contributing to HSC heterogeneity.

Graphical abstract

Teaser

Doi et al. show that hematopoietic stem cells (HSCs) with robust lymphopoietic and long-term reconstituting capability express special AT-rich sequence-binding protein 1 (SATB1). SATB1-expressing and non-expressing HSCs are interconvertible. Moreover, they provide insights into the heterogeneity of HSCs, which are correlated with changes in SATB1 expression levels.


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