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UM171 promotes expansion of autologous peripheral blood hematopoietic stem cells from poorly mobilizing lymphoma patients |
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| Institution: | 1. Academy of Military Medical Sciences, Academy of Military Sciences, Beijing 100850, PR China;2. Department of Hematopoietic Stem Cell Transplantation, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, PR China;3. Beijing Key Laboratory of Stem Cell Therapy and Transformation Research, Beijing 100071, PR China;4. The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, PR China;5. Department of Hematology and Rheumatology, Zhanjiang Central Hospital, Guangdong Medical University, Zhanjiang 524045, PR China |
| Abstract: | BackgroundAutologous hematopoietic stem cell transplantation is an effective therapeutic strategy for lymphoma patients. However, some patients have to give up receiving transplantation because of failing to obtain sufficient CD34+ cells yields. Therefore, we ex vivo expanded HSCs of lymphoma patients using UM171 to solve the problem of HSCs deficiency.MethodsMobilized peripheral blood-derived CD34+ cells from lymphoma patients were cultured for 10 days with or without UM171. The fold of cell expansion and the immunophenotype of expanded cells were assessed by flow cytometry. RNA-seq experiment was performed to identify the mechanism by which UM171 promoted HSCs expansion.ResultsUM171 treatment increased the proportion of CD34+ (68.97 ± 6.91%), CD34+ CD38? cells (44.10 ± 9.20%) and CD34+CD38?CD45RA?CD90+ LT-HSCs (3.05 ± 2.08%) compared to vehicle treatment (36.08 ± 11.14%, 18.30 ± 9.49% and 0.56 ± 0.45%, respectively). UM171 treatment led to an 85.08-fold increase in LT-HSC numbers relative to initial cells. Importantly, UM171 promoted expansion of LT-HSCs achieved 138.57-fold in patients with poor mobilization. RNA-seq data showed that UM171 upregulated expression of HSC-, mast cell-specific genes and non-canonical Wnt signaling related genes, and inhibited genes expression of erythroid, megakaryocyte and inflammatory mediated chemokine.ConclusionsOur study shows that UM171 can efficiently promote ex vivo expansion of HSCs from lymphoma patients, especially for poorly mobilizing patients. In terms of mechanism, UM171 upregulate HSC-specific genes expression and suppress erythroid and megakaryocytic differentiation, as well as activate non-classical Wnt signaling. |
| Keywords: | Hematopoietic stem cells Small molecules UM171 Expansion Lymphoma AHSCT"} {"#name":"keyword" "$":{"id":"k0035"} "$$":[{"#name":"text" "_":"Autologous hematopoietic stem cell transplantation HSC"} {"#name":"keyword" "$":{"id":"k0045"} "$$":[{"#name":"text" "_":"Hematopoietic stem cell HSPCs"} {"#name":"keyword" "$":{"id":"k0055"} "$$":[{"#name":"text" "_":"Hematopoietic stem and progenitor cells LT-HSCs"} {"#name":"keyword" "$":{"id":"k0065"} "$$":[{"#name":"text" "_":"Long-term HSCs mPB"} {"#name":"keyword" "$":{"id":"k0075"} "$$":[{"#name":"text" "_":"Mobilized peripheral blood CB"} {"#name":"keyword" "$":{"id":"k0085"} "$$":[{"#name":"text" "_":"Cord blood SR1"} {"#name":"keyword" "$":{"id":"k0095"} "$$":[{"#name":"text" "_":"Stem Regenin 1 DLBCL"} {"#name":"keyword" "$":{"id":"k0105"} "$$":[{"#name":"text" "_":"Diffuse large B cell lymphoma BL"} {"#name":"keyword" "$":{"id":"k0115"} "$$":[{"#name":"text" "_":"Burkitt lymphoma HL"} {"#name":"keyword" "$":{"id":"k0125"} "$$":[{"#name":"text" "_":"Hodgkin's lymphoma PBSCs"} {"#name":"keyword" "$":{"id":"k0135"} "$$":[{"#name":"text" "_":"Peripheral blood stem cells CFU"} {"#name":"keyword" "$":{"id":"k0145"} "$$":[{"#name":"text" "_":"Colony-forming unit PR"} {"#name":"keyword" "$":{"id":"k0155"} "$$":[{"#name":"text" "_":"Partial remission CR"} {"#name":"keyword" "$":{"id":"k0165"} "$$":[{"#name":"text" "_":"Complete remission TNC"} {"#name":"keyword" "$":{"id":"k0175"} "$$":[{"#name":"text" "_":"Total nucleated cells BFU"} {"#name":"keyword" "$":{"id":"k0185"} "$$":[{"#name":"text" "_":"Burst-forming units-erythroid G"} {"#name":"keyword" "$":{"id":"k0195"} "$$":[{"#name":"text" "_":"Granulocyte M"} {"#name":"keyword" "$":{"id":"k0205"} "$$":[{"#name":"text" "_":"Macrophage GM"} {"#name":"keyword" "$":{"id":"k0215"} "$$":[{"#name":"text" "_":"Granulocyte-macrophage E"} {"#name":"keyword" "$":{"id":"k0225"} "$$":[{"#name":"text" "_":"Erythrocyte GEMM"} {"#name":"keyword" "$":{"id":"k0235"} "$$":[{"#name":"text" "_":"Granulocyte/ erythrocyte/macrophage/ megakaryocyte ROS"} {"#name":"keyword" "$":{"id":"k0245"} "$$":[{"#name":"text" "_":"Reactive oxygen species GO"} {"#name":"keyword" "$":{"id":"k0255"} "$$":[{"#name":"text" "_":"Gene Ontology RNA-seq"} {"#name":"keyword" "$":{"id":"k0265"} "$$":[{"#name":"text" "_":"RNA sequencing DEGs"} {"#name":"keyword" "$":{"id":"k0275"} "$$":[{"#name":"text" "_":"Differentially expressed genes |
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