Center for Preclinical Studies and Technology, Laboratory of Regenerative Medicine, Medical University of Warsaw, Warsaw, Poland.
Stem Cell Institute at Division of Hemtatology, Graham Brown Cancer Center, University of Louisville, 500 S. Floyd Street, Rm. 107, Louisville, KY, 40202, USA.
Stem Cell Rev Rep. 2023 Oct;19(7):2292-2298. doi: 10.1007/s12015-023-10581-7. Epub 2023 Jun 29.
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.
骨髓（BM）不仅含有造血干细胞（HSCs），还含有一些非常罕见的、早期发育的、静止的小干细胞，这些细胞在激活后可能会跨谱系分化。这些小细胞被命名为非常小的胚胎样干细胞（VSELs），可以分化为包括 HSCs 在内的多种类型的细胞。有趣的是，鼠类 BM 中也存在一种“神秘”的小 CD45 干细胞群体，其具有许多与静止 HSCs 相关的表型特征。由于“神秘”群体细胞的大小介于 VSELs 和 HSCs 之间，并且 CD45 VSELs 可以分化为 CD45 HSCs，因此我们假设静止的 CD45“神秘”群体可能是 VSELs 和 HSCs 之间缺失的发育联系。为了支持这一假设，我们发现 VSELs 在获得已经在“神秘”干细胞上表达的 CD45 抗原的表达后，首先富集 HSCs。此外，从 BM 中分离出的类似于“神秘”群体细胞的新鲜 VSELs 处于静止状态，在体外和体内实验中均不显示造血潜能。然而，我们注意到，类似于 CD45 VSELs，CD45“神秘”群体细胞在与 OP9 基质共培养后被指定为 HSCs。我们还发现，Oct-4 的 mRNA，一种高度表达于 VSELs 的多能性标志物，也可在“神秘”群体细胞中检测到，尽管水平要低得多。最后，我们确定在 OP9 基质上指定的“神秘”群体细胞支持的细胞能够植入并在致死性照射的受体中建立造血嵌合体。基于这些结果，我们提出鼠类 BM“神秘”群体可能是 BM 中驻留的 VSELs 和已经指定用于淋巴造血谱系的 HSCs 之间的中间群体。
