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Exponential expansion of CD34+ cells in response to StemRegenin-1 occurs with minimal changes in gene expression

ABSTRACT: Hematopoietic stem/progenitor cell transplantation (HSCT) is a well-established treatment option for hematological and other disorders. Umbilical cord blood (UCB) is a rich source of hematopoietic stem and progenitor cells (HSPCs). Cluster of Differentiation (CD)34 is commonly used as a cell surface marker to identify and isolate HSPCs. Transplantation using a single UCB unit may be associated with delayed hematopoietic reconstitution as it may not contain a sufficient number of HSPCs required for adult transplantation. One way of overcoming this limitation is through ex vivo expansion of UCB-derived HSPCs using the aryl hydrocarbon receptor (AhR) antagonist, StemRegenin-1 (SR1), which promotes the expansion of HSPCs. Our study investigated the effects of SR1 on the transcriptome of expanded CD34+ cells from UCB, and we also report on a comparison between the transcriptome profiles of 7-day expanded and non-expanded CD34+ cells. CD34+ HSPCs expanded with SR1 for 7 days displayed two significantly downregulated genes, cytochrome P450, family 1, subfamily B, polypeptide 1 (CYP1B1) and erythrocyte membrane protein band 4.1-like 3 (EPB41L3), when compared to controls (without SR1). Transcriptome analysis of CD34+ HSPCs expanded for 7 days using SR1 revealed that 391 genes were significantly upregulated, while 456 genes were significantly downregulated when compared to non-expanded CD34+ cells. In conclusion, though hundreds of genes were differentially expressed between SR1-expanded and non-expanded CD34+ HSPCs, only two genes were significantly downregulated in cells expanded for 7 days with SR1 versus control at the same time point (without SR1).

ORGANISM(S): Homo sapiens

PROVIDER: GSE146810 | GEO | 2024/09/25

REPOSITORIES: GEO

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Project description:Purpose: We designed this study to evaluate the feasibility of using only one factor to respecify human induced pluripotent stem cells (iPSCs)-derived blood cells into long-term engraftable hematopoietic stem and progenitor cells (HSPCs). We also parallelly compared iPSC-derived HSPCs (iHSPCs) with primary HSPCs under the same induction and transplantation condition in order to examine the functional equivalency between iHSPCs and bona fide HSPCs. Methods: In vitro derived human iPSC-HSPCs are induced with or without (w/o) doxycycline for the expression of MLL-AF4. In vivo derived bone marrow cells are harvested and FACS-sorted for human populations from primary transplants over nine to sixteen weeks after transplantation. Either iPSC-HSPCs or primary HSPCs, both of which are induced by MLL-AF4, is used for the transplantation experiments. iPSCs are either derived from peripheral blood mobilized CD34+ HSPCs (CD34-iPSC) or mononuclear cells (MN-iPSCs). Normal human CD34+ HSPCs and mononuclear cells are set as control groups. Results: MLL-AF4 can impart HSC and lymphoid potential to iPSC-derived blood cells in vitro, and induction of MLL-AF4 leads to the cellular identity transition from common myeloid progenitors to hematopoietic stem and progenitor cells. MLL-AF4 alone is sufficient to realize the potent engraftment of induced HSPCs (iHSPCs) from iPSCs, and multilineage and long-term hematopoiesis could be observed. Primary HSPCs with the induction of MLL-AF4 could gain significantly enhanced engraftability. During the long-term engraftment period, leukemic mutations with a bias to B-cell leukemia could be found in the iHSPCs and their derivatives. By contrast, MLL-AF4 induced primary HSPCs maintain the normal hematopoiesis without leukemic transformation. Conclusions: Our study has demonstrated for the first time, to our knowledge, that the pluripotency-dependent conversion of somatic cells to long-term engraftable HSPCs can be achieved by using a single factor in a non-integrative way. This study also suggests that iPSC-derived HSPCs are more prone to leukemic mutations during the long-term engraftment period, which provides a necessary caveat of using them in the actual therapies.

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Exponential expansion of CD34+ cells in response to StemRegenin-1 occurs with minimal changes in gene expression

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