Abstract
The bone marrow (BM) niche regulates multiple hematopoietic stem cell (HSC) processes. Clinical treatment for hematological malignancies by HSC transplantation often requires preconditioning via total body irradiation, which severely and irreversibly impairs the BM niche and HSC regeneration. Novel strategies are needed to enhance HSC regeneration in irradiated BM. We compared the effects of EGF, FGF2, and PDGFB on HSC regeneration using human mesenchymal stem cells (MSCs) that were transduced with these factors via lentiviral vectors. Among the above niche factors tested, MSCs transduced with PDGFB (PDGFB-MSCs) most significantly improved human HSC engraftment in immunodeficient mice. PDGFB-MSC-treated BM enhanced transplanted human HSC self-renewal in secondary transplantations more efficiently than GFP-transduced MSCs (GFP-MSCs). Gene set enrichment analysis showed increased antiapoptotic signaling in PDGFB-MSCs compared with GFP-MSCs. PDGFB-MSCs exhibited enhanced survival and expansion after transplantation, resulting in an enlarged humanized niche cell pool that provide a better humanized microenvironment to facilitate superior engraftment and proliferation of human hematopoietic cells. Our studies demonstrate the efficacy of PDGFB-MSCs in supporting human HSC engraftment.
Highlights
These authors contributed : Xiuxiu Yin, Linping Hu
2.6–3.0 × CB-CD34+ cells mixed with 5 × GFPMSCs, EGF-mesenchymal stem cells (MSCs), FGF2-MSCs or PDGFB-MSCs were injected into the right tibia
This discrepancy may be due to several reasons: (1) we reduced the number of transplanted MSCs: In our preliminary experiment, we cotransplanted human CD34+ cells with 1 × 106 MSCs according to these previous studies
Summary
We aimed to improve human hematopoietic engraftment using humanized niche cells. We aimed to enhance the functionality of MSCs by overexpressing human EGF, FGF2, or PDGFB
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