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Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock
Mantel, Charlie R.,O'Leary, Heather A.,Chitteti, Brahmananda R.,Huang, X.,Cooper, S.,Hangoc, G.,Brustovetsky, N.,Srour, Edward F.,Lee, M.,Messina-Graham, S.,Haas, David M.,Falah, N.,Kapur, R.,Pelus, L Cell Press ; MIT Press 2015 Cell Vol.161 No.7
Hematopoietic stem cells (HSCs) reside in hypoxic niches within bone marrow and cord blood. Yet, essentially all HSC studies have been performed with cells isolated and processed in non-physiologic ambient air. By collecting and manipulating bone marrow and cord blood in native conditions of hypoxia, we demonstrate that brief exposure to ambient oxygen decreases recovery of long-term repopulating HSCs and increases progenitor cells, a phenomenon we term extraphysiologic oxygen shock/stress (EPHOSS). Thus, true numbers of HSCs in the bone marrow and cord blood are routinely underestimated. We linked ROS production and induction of the mitochondrial permeability transition pore (MPTP) via cyclophilin D and p53 as mechanisms of EPHOSS. The MPTP inhibitor cyclosporin A protects mouse bone marrow and human cord blood HSCs from EPHOSS during collection in air, resulting in increased recovery of transplantable HSCs. Mitigating EPHOSS during cell collection and processing by pharmacological means may be clinically advantageous for transplantation.
Mantel, Charlie,Guo, Ying,Lee, Man Ryul,Kim, Min-Kyoung,Han, Myung-Kwan,Shibayama, Hirohiko,Fukuda, Seiji,Yoder, Mervin C.,Pelus, Louis M.,Kim, Kye-Seong,Broxmeyer, Hal E. American Society of Hematology 2007 Blood Vol.109 No.10
<B>Abstract</B><P>Karyotypic abnormalities in cultured embryonic stem cells (ESCs), especially near-diploid aneuploidy, are potential obstacles to ESC use in regenerative medicine. Events causing chromosomal abnormalities in ESCs may be related to events in tumor cells causing chromosomal instability (CIN) in human disease. However, the underlying mechanisms are unknown. Using multiparametric permeabilized-cell flow cytometric analysis, we found that the mitotic-spindle checkpoint, which helps maintain chromosomal integrity during all cell divisions, functions in human and mouse ESCs, but does not initiate apoptosis as it does in somatic cells. This allows an unusual tolerance to polyploidy resulting from failed mitosis, which is common in rapidly proliferating cell populations and which is reduced to near-diploid aneuploidy, which is also common in human neoplastic disease. Checkpoint activation in ESC-derived early-differentiated cells results in robust apoptosis without polyploidy/aneuploidy similar to that in somatic cells. Thus, the spindle checkpoint is “uncoupled” from apoptosis in ESCs and is a likely source of karyotypic abnormalities. This natural behavior of ESCs to tolerate/survive varying degrees of ploidy change could complicate genome-reprogramming studies and stem-cell plasticity studies, but could also reveal clues about the mechanisms of CIN in human tumors.</P>
Cells enter a unique intermediate 4N stage, not 4N-G1, after aborted mitosis.
Mantel, Charlie,Guo, Ying,Lee, Man Ryul,Han, Myung Kwan,Rhorabough, Sara,Kim, Kye Seong,Broxmeyer, Hal E Landes Bioscience 2008 Cell Cycle Vol.7 No.4
<P>It is widely accepted that mammalian cells enter the next G(1)-phase (G(1)) with 4N DNA after slippage from prolonged drug-induced mitotic block caused by activation of the transient spindle checkpoint. Understanding cell fate after mitotic slippage (MS) has significant clinical importance. The conclusion the MS cells enter 4N-G(1) is based on morphology and mitotic cyclin destruction. Definitive biochemical evidence for G(1) is scarce or unconvincing, in part because of methods of protein extraction required for immunoblot analysis that cannot take into account the cell cycle heterogeneity of cell cultures. We used single-cell-intracellular-flow-cytometric analysis to further define important factors determining cell fate after MS. Results from human and mouse embryonic stem cells (ESC) that reenter polyploid cell cycles are compared to human somatic cells that die after MS. We conclude that phosphorylation status of pRb, p53, CDK1, and especially cyclin B1 levels are important for cell fate decision in MS cells, which occur in a unique, intervening, non-G(1), tetraploid subphase.</P>
Metabolome Profiling of Partial and Fully Reprogrammed Induced Pluripotent Stem Cells
Park, Soon-Jung,Lee, Sang A,Prasain, Nutan,Bae, Daekyeong,Kang, Hyunsu,Ha, Taewon,Kim, Jong Soo,Hong, Ki-Sung,Mantel, Charlie,Moon, Sung-Hwan,Broxmeyer, Hal E.,Lee, Man Ryul Mary Ann Liebert 2017 STEM CELLS AND DEVELOPMENT Vol.26 No.10