Abstract
Expansion of hematopoietic stem cells (HSCs) is a ‘holy grail’ of regenerative medicine, as successful stem cell transplantations depend on the number and quality of infused HSCs. Although many attempts have been pursued to either chemically or genetically increase HSC numbers, neither clonal analysis of these expanded cells nor their ability to support mature blood lineages has been demonstrated. Here we show that miR-125a, at the single cell level, can expand murine long-term repopulating HSCs. In addition, miR-125a increases clone longevity, clone size and clonal contribution to hematopoiesis. Unexpectedly, we found that miR-125a expanded HSCs clones were highly homogenously distributed across multiple anatomical sites. Interestingly, these miR-125a overexpressing cells had enhanced mobility and were more frequently detected in the spleen. Our study reveals a novel, cell-intrinsically controlled mechanism by which HSC migration is regulated.
Highlights
Hematopoietic stem cell (HSC) transplantation constitutes an important treatment modality for multiple hematological disorders, including leukemia
We refer to clones as “consistent” if they were reproducibly detected in series of at least 2 consecutive samples. In this case no restrictions were made on their actual contribution to blood production. Using this parameter we counted up to 50 clones in mice transplanted with LT-HSCs or progenitors transduced with CV at week 4 post-transplant, whereas up to 200 clones were detected in mice transplanted with miR-125a OE cells (Fig. 1C)
We identified cells with a clonogenic potential in the peripheral blood in miR-125a transplanted mice during steady state hematopoiesis. This strongly indicated that miR-125a causes enhanced HSC trafficking from the bone marrow (BM) to the circulation
Summary
Hematopoietic stem cell (HSC) transplantation constitutes an important treatment modality for multiple hematological disorders, including leukemia. To identify molecular contributors to these genetically regulated qualitative and quantitative HSC-intrinsic differences, we performed genome-wide mRNA6 and microRNA7 expression studies The latter analysis revealed an increased expression of the microRNA-99b-let7e-125a cluster in the DBA/2 strain, a strain that displays increased HSC numbers and enhanced mobilization compared to C57BL/67. To develop alternative strategies to improve hematopoietic reconstitution after transplant, we recently showed that it is feasible to induce functional stem cell activity in progenitors, which are normally devoid of long-term repopulating potential by enforcing expression of miR-125a in committed progenitors. Mir-125a strongly increased HSC clone number, clone size, clone longevity, and migration, leading to symmetrical distribution of clones throughout the skeleton These cells showed increased responsiveness to G-CSF in vitro and in vivo and downregulation of c-Kit expression. We employed a mathematical model, which suggested that an increased self-renewal and slower differentiation rate of HSCs overexpressing miR-125a contribute to their expansion
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