Zeb1 Regulates the Function of Lympho-Myeloid Primed Progenitors after Transplantation

Alhomidi Almotiri; Ashleigh S Boyd; Neil P Rodrigues

doi:10.3390/biom13091386

Zeb1 Regulates the Function of Lympho-Myeloid Primed Progenitors after Transplantation

Biomolecules. 2023 Sep 14;13(9):1386. doi: 10.3390/biom13091386.

Authors

Alhomidi Almotiri^{1

2}, Ashleigh S Boyd^{3

4}, Neil P Rodrigues²

Affiliations

¹ Department of Clinical Laboratory Sciences, College of Applied Medical Sciences-Dawadmi, Shaqra University, Dawadmi 17464, Saudi Arabia.
² European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK.
³ Department of Surgical Biotechnology, Division of Surgery and Interventional Science, Royal Free Hospital, University College London, London NW3 2PS, UK.
⁴ Institute of Immunity and Transplantation, University College London, London NW3 2PP, UK.

Abstract

Zeb1, a zinc finger E-box binding homeobox epithelial-mesenchymal (EMT) transcription factor, acts as a critical regulator of hematopoietic stem cell (HSC) self-renewal and multi-lineage differentiation. Whether Zeb1 directly regulates the function of multi-potent progenitors primed for hematopoietic lineage commitment remains ill defined. By using an inducible Mx-1 Cre conditional mouse model where Zeb1 was genetically engineered to be deficient in the adult hematopoietic system (hereafter Zeb1^-/-), we found that the absolute cell number of immunophenotypically defined lympho-myeloid primed progenitors (LMPPs) from Zeb1^-/- mice was reduced. Myeloid- and lymphoid-biased HSCs in Zeb1^-/- mice were unchanged, implying that defective LMPP generation from Zeb1^-/- mice was not directly caused by an imbalance of lineage-biased HSCs. Functional analysis of LMPP from Zeb1^-/- mice, as judged by competitive transplantation, revealed an overall reduction in engraftment to hematopoietic organs over 4 weeks, which correlated with minimal T-cell engraftment, reduced B-cell and monocyte/macrophage engraftment, and unperturbed granulocyte engraftment. Thus, Zeb1 regulates LMPP differentiation potential to select lympho-myeloid lineages in the context of transplantation.

Keywords: Zeb1; differentiation; hematopoiesis.

Grants and funding

This work is supported by the Leukemia Cancer Society (to N.P.R.), Saudi Arabian Cultural Bureau (to A.A. and N.P.R.), and Shaqra University (to A.A.). The Rodrigues laboratory is also supported by Blood Cancer UK.