The "Mystery Cell Population" Residing in Murine Bone Marrow - A Missing Link Between Very Small Embryonic Like Stem Cells and Hematopoietic Stem Cells?

Kamila Bujko; Malwina Suszynska; Stephanie Franczak; Magdalena Kucia; Mariusz Z Ratajczak; Janina Ratajczak

doi:10.1007/s12015-023-10581-7

The "Mystery Cell Population" Residing in Murine Bone Marrow - A Missing Link Between Very Small Embryonic Like Stem Cells and Hematopoietic Stem Cells?

Stem Cell Rev Rep. 2023 Oct;19(7):2292-2298. doi: 10.1007/s12015-023-10581-7. Epub 2023 Jun 29.

Authors

Kamila Bujko^{1

2}, Malwina Suszynska², Stephanie Franczak¹, Magdalena Kucia¹, Mariusz Z Ratajczak^{3

4}, Janina Ratajczak⁵

Affiliations

¹ Center for Preclinical Studies and Technology, Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland.
² Stem Cell Institute at Division of Hemtatology, Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA.
³ Center for Preclinical Studies and Technology, Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland. mzrata01@louisville.edu.
⁴ Stem Cell Institute at Division of Hemtatology, Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA. mzrata01@louisville.edu.
⁵ Stem Cell Institute at Division of Hemtatology, Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA. j0rata01@louisville.edu.

Abstract

Bone marrow (BM) contains not only hematopoietic stem cells (HSCs) but also some very rare, early development, small quiescent stem cells that, upon activation, may differentiate across germlines. These small cells, named very small embryonic like stem cells (VSELs), can undergo specification into several types of cells including HSCs. Interestingly, murine BM is also home to a "mystery" population of small CD45⁺ stem cells with many of the phenotypic characteristics attributed to resting HSCs. Since the size of the "mystery" population cells are between that of VSELs and HSCs, and because CD45^- VSELs can be specified into CD45⁺ HSCs, we hypothesized that the quiescent CD45⁺ "mystery" population could be a missing developmental link between VSELs and HSCs. To support this hypothesis, we showed that VSELs first became enriched for HSCs after acquiring expression of the CD45 antigen already expressed on "mystery" stem cells. Moreover, VSELs freshly isolated from BM similar to the "mystery" population cells, are quiescent and do not reveal hematopoietic potential in in vitro and in vivo assays. However, we noticed that CD45⁺ "mystery" population cells, similar to CD45^- VSELs, became specified into HSCs after co-culture over OP9 stroma. We also found that mRNA for Oct-4, a pluripotency marker that is highly expressed in VSELs, is also detectable in the "mystery" population cells, albeit at a much lower level. Finally, we determined that the "mystery" population cells specified over OP9 stroma support were able to engraft and establish hematopoietic chimerism in lethally irradiated recipients. Based on these results, we propose that the murine BM "mystery" population could be an intermediate population between BM-residing VSELs and HSCs already specified for lympho-hematopoietic lineages.

Keywords: BM stem cells; Hematopoietic reconstitution; Hematopoietic specification; Markers of pluripotency; Mystery population stem cells; VSELs.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Marrow Cells
Bone Marrow*
Cell Differentiation
Embryonic Stem Cells
Hematopoietic Stem Cells*
Mice