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Coinhibition of activated p38 MAPK? and mTORC1 potentiates stemness maintenance of HSCs from SR1-expanded human cord blood CD34⁺ cells via inhibition of senescence.

ABSTRACT: The stemness of ex vivo expanded hematopoietic stem cells (HSCs) is usually compromised by current methods. To explore the failure mechanism of stemness maintenance of human HSCs, which were expanded from human umbilical cord blood (hUCB) CD34⁺ cells, by differentiation inhibitor Stem Regenin 1 (SR1), an antagonist of aryl hydrocarbon receptor, we investigated the activity of p38 mitogen-activated protein kinase ? (p38 MAPK?, p38?) and mammalian target of rapamycin complex 1 (mTORC1), and their effect on SR1-expanded hUCB CD34⁺ cells. Our results showed that cellular senescence occurred in the SR1-expanded hUCB CD34⁺ cells in which p38? and mTORC1 were successively activated. Furthermore, their coinhibition resulted in a further decrease in hUCB CD34⁺ cell senescence without an effect on apoptosis, promoted the maintenance of expanded phenotypic HSCs without differentiation inhibition, increased the hematopoietic reconstitution ability of multiple lineages, and potentiated the long-term self-renewal capability of HSCs from SR1-expanded hUCB CD34⁺ cells in NOD/Shi-scid/IL-2R?^null mice. Our mechanistic study revealed that senescence inhibition by our strategy was mainly attributed to downregulation of the splicesome, proteasome formation, and pyrimidine metabolism signaling pathways. These results suggest that coinhibition of activated p38? and mTORC1 potentiates stemness maintenance of HSCs from SR1-expanded hUCB CD34⁺ cells via senescence inhibition. Thus, we established a new strategy to maintain the stemness of ex vivo differentiation inhibitor-expanded human HSCs via coinhibition of multiple independent senescence initiating signal pathways. This senescence inhibition-induced stemness maintenance of ex vivo expanded HSCs could also have an important role in other HSC expansion systems.

SUBMITTER: Li X

PROVIDER: S-EPMC7695631 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Coinhibition of activated p38 MAPKα and mTORC1 potentiates stemness maintenance of HSCs from SR1-expanded human cord blood CD34<sup>+</sup> cells via inhibition of senescence.

Li Xiaoyi X Ma Xiao X Chen Ying Y Peng Danyue D Wang Huifang H Chen Suhua S Xiao Yin Y Li Lei L Zhou Hao H Cheng Fanjun F Gao Yingdai Y Chang Jiwei J Cheng Tao T Liu Lingbo L

Stem cells translational medicine 20200629 12

The stemness of ex vivo expanded hematopoietic stem cells (HSCs) is usually compromised by current methods. To explore the failure mechanism of stemness maintenance of human HSCs, which were expanded from human umbilical cord blood (hUCB) CD34<sup>+</sup> cells, by differentiation inhibitor Stem Regenin 1 (SR1), an antagonist of aryl hydrocarbon receptor, we investigated the activity of p38 mitogen-activated protein kinase α (p38 MAPKα, p38α) and mammalian target of rapamycin complex 1 (mTORC1), ...[more]

PMID: 32602209

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Project description:BackgroundHematopoietic stem cell (HSC) transplantation has been widely applied to the treatment of malignant blood diseases. However, limited number of functional HSCs hinders successful transplantation. The purpose of our current study is to develop a new and cost-efficient medium formulation that could greatly enhance the expansion of HSCs while retaining their long-term repopulation and hematopoietic properties for effective clinical transplantation.MethodsEnriched human CD34+ cells and mobilized nonhuman primate peripheral blood CD34+ cells were expanded with a new, cost-efficient expansion medium formulation, named hematopoietic expansion medium (HEM), consisting of various cytokines and nutritional supplements. The long-term repopulation potential and hematologic-lineage differentiation ability of expanded human cells were studied in the non-obese diabetic/severe combined immunodeficiency mouse model. Furthermore, the efficacy and safety studies were performed by autologous transplantation of expanded primate cells in the nonhuman primate model.ResultsHEM could effectively expand human CD34+ cells by up to 129 fold within 9 days. Expanded HSCs retained long-term repopulation potential and hematologic-lineage differentiation ability, as indicated by (1) maintenance (over unexpanded HSCs) of immunophenotypes of CD38-CD90+CD45RA-CD49f+ in CD34+ cells after expansion; (2) significant presence of multiple human hematopoietic lineages in mouse peripheral blood and bone marrow following primary transplantation; (3) enrichment (over unexpanded HSCs) in SCID-repopulating cell frequency measured by limiting dilution analysis; and (4) preservation of both myeloid and lymphoid potential among human leukocytes from mouse bone marrow in week 24 after primary transplantation or secondary transplantation. Moreover, the results of autologous transplantation in nonhuman primates demonstrated that HEM-expanded CD34+ cells could enhance hematological recovery after myelo-suppression. All primates transplanted with the expanded autologous CD34+ cells survived for over 18 months without any noticeable abnormalities.ConclusionsTogether, these findings demonstrate promising potential for the utility of HEM to improve expansion of HSCs for clinical application.

Dataset Information

Coinhibition of activated p38 MAPK? and mTORC1 potentiates stemness maintenance of HSCs from SR1-expanded human cord blood CD34⁺ cells via inhibition of senescence.

Publications

Coinhibition of activated p38 MAPKα and mTORC1 potentiates stemness maintenance of HSCs from SR1-expanded human cord blood CD34<sup>+</sup> cells via inhibition of senescence.

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Dataset Information

Coinhibition of activated p38 MAPK? and mTORC1 potentiates stemness maintenance of HSCs from SR1-expanded human cord blood CD34+ cells via inhibition of senescence.

Publications

Coinhibition of activated p38 MAPKα and mTORC1 potentiates stemness maintenance of HSCs from SR1-expanded human cord blood CD34<sup>+</sup> cells via inhibition of senescence.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Coinhibition of activated p38 MAPK? and mTORC1 potentiates stemness maintenance of HSCs from SR1-expanded human cord blood CD34⁺ cells via inhibition of senescence.