scholarly journals Cyclosporine May Inhibit the Effect of Extra-Physiologic Oxygen Shock/Stress on Peripheral Blood Stem Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3346-3346
Author(s):  
Amro Elshoury ◽  
Hans Minderman ◽  
Alexis Conway ◽  
Paul K. Wallace ◽  
Charlie Mantel ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell Differentiation ◽  
Ambient Air ◽  
Peripheral Blood Stem Cells ◽  
Human Cord Blood ◽  
Murine Bone Marrow ◽  
Blood Stem Cells ◽  
Shock Stress

Abstract Introduction: Adequate numbers of stem cells with preserved multi-potency and self-renewing capabilities are necessary for successful hematopoietic reconstitution after bone marrow transplantation. Although hematopoietic stem cells (HSC) reside in the bone marrow under a hypoxic microenvironment (1-4% O2), human HSC are collected and processed in ambient air (21% O2) (Spencer et al., Nature 508:269-73). Exposure of murine bone marrow and human cord blood to ambient air for as little as 30 minutes triggered stem cell differentiation from quiescent pluripotent long term stem cells into activated multipotent progenitors (MPPs), a phenomenon called extra-physiologic oxygen shock / stress (EPHOSS)(Mantel et al., Cell 161:1553-65). The effect of EPHOSS on HSCs is mediated through reactive oxygen species (ROS) which open the mitochondrial permeability transition pore (MPTP) and trigger stem cell differentiation. Cyclosporine (CSA) inhibits the MPTP regulator cyclophilin D and prevents MPTP opening (Kroemer et al., Physiol Rev 87:99-163). Currently, mobilized peripheral blood stem cells (PBSCs) are the major source of grafts for hematopoietic cell transplantation. We hypothesized that EPHOSS is detrimental to human PBSCs similar to murine bone marrow and human cord blood stem cells and CSA will protect human PBSCs from the effects of EPHOSS and inhibit their differentiation from pluripotent long term HSC into short term MPPs. Study design and methods. This is a proof-of-concept, prospective, non-interventional study. We obtained G-CSF mobilized PBSCs from healthy related donors under an IRB approved protocol. All donors provided written informed consent. Blood containing HSCs was collected from each donor with minimal exposure to ambient air (<60 seconds). The sample was immediately split and incubated for 60 minutes with and without CSA (50 µg/mL). CSA treated and untreated PBSCs were immunophenotyped by multi-parameter flow cytometry for HSCs (CD34+CD38-CD90+CD45RA-), MPP (CD34+CD38-CD90-CD45RA-) and common lymphoid progenitors (CD34+CD38+CD127+). We used a CD34 ISHAGE-based gating strategy to accurately enumerate HSC and MPP. Results. In four separate experiments, CSA treated PBSCs had a higher median (range) number of HSCs/106 total nucleated cells (TNC) compared to untreated PBSCs ((297 (51 - 512) versus 185 (47 -392), respectively). CSA treated PBSCs also had a higher median (range) HSC:MPP ratio compared to untreated PBSCs ((0.56 (0.40 - 0.70) versus 0.43 (0.30 - 0.50), respectively) suggesting that the differentiation of HSC to MPP upon exposure to air was decreased in the CSA treated PBSCs. Conclusions / future directions. This is the first report describing the effect of EPHOSS in human PBSCs. Our preliminary data suggest that EPHOSS promotes the differentiation of human PBSCs from HSC to MPP and that CSA may inhibit this process. Further confirmatory and mechanistic studies exploring the contribution of MPTP and ROS to EPHOSS are ongoing. The results from this research may potentially change the current practice of collecting PBSCs in ambient air. Disclosures McCarthy: Janssen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria. Chen:Bellicum Pharmaceuticals: Research Funding.

Dipeptidyl Peptidase 4 (DPP4) Is Altered By, and Modulates Sensitivity to, Extra-Physiologic Oxygen Shock Stress (EPHOSS): Implications for Hematopoietic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2361-2361
Author(s):  
Heather A. O'Leary ◽  
Thomas McNamara ◽  
Hal E. Broxmeyer
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Ambient Air ◽  
Mouse Bone Marrow ◽  
Human Cord Blood ◽  
Hematopoietic Stem ◽  
Dipeptidyl Peptidase 4 ◽  
Expression Activity ◽  
Shock Stress

Abstract Hematopoietic stem cells (HSC) reside in hypoxic niches (~1-4% O2), however, HSC studies are consistently performed using cells isolated in ambient air (~20% O2), regardless of subsequent processing in low oxygen tension. We recently published that by collecting/processing stem cells in physiologically native conditions of hypoxia, with all procedures performed inside a hypoxic chamber (3% O2), we enhance the recovery of phenotypic, and functional, self-renewing long-term repopulating HSC (LT-HSC) with concomitantly decreasing numbers of progenitor cells. This occurs by inhibiting damage due to brief exposure of mouse bone marrow (BM) or human cord blood (CB) cells to ambient oxygen (a phenomenon we term Extra Physiologic Oxygen Shock/Stress (EPHOSS)) which we, in part, mechanistically linked to mitochondrial permeability transition pore (MPTP), Reactive Oxygen Species (ROS) and cyclophilin D. This data suggests that true numbers of HSCs, and the transplantation potency of BM and CB, have been consistently underestimated due to rapid differentiation of LT-HSCs in ambient air (EPHOSS), but the broad effects of EPHOSS on stem cell phenotype are unknown. We hypothesized that Dipeptidyl Peptidase 4 (DPP4) may be altered by EPHOSS and involved in the effects of EPHOSS on HSC. We showed that DPP4, a serine peptidase whose enzymatic activity leads to the N terminal cleavage of select penultimate amino acids of proteins, alters homing and engraftment of HSC and the number of cytokines, chemokines and growth factors that have putative DPP4 truncation sites have been dramatically underestimated. Functional and mechanistic roles of full length (FL) versus DPP4 truncated (T) factors, the ability of DPP4 T proteins to induce signaling that FL factors cannot, and the effects of EPHOSS on DPP4 expression/activity, and vice versa, have not been investigated and may have yet unappreciated clinical application. Here we present novel data demonstrating that mouse bone marrow harvested in air in the presence of Diprotin A, a DPP4 inhibitor, or from DPP4 K/O mice, results in a significant increase in the number of phenotypic LT-HSC (p=.017), suggesting that inhibition of DPP4 can diminish the loss of phenotypic LT-HSC due to EPHOSS. Further, the percentage of DPP4+ cells is significantly increased in primitive fractions of mouse bone marrow and human cord blood (LSK ~15% DPP4+, LSKCD150+ ~40%DPP4+, CD34+CD38- of CB ~10% DPP4+, CD34+CD38-CD45RA-CD90+CD49F+ ~40% DPP4+, p=.007), the numbers of DPP4+ cells are additionally enhanced 15- 20% when cells (BM and hCB) are isolated in hypoxia, especially in the LT-HSC fraction (Air 40% DPP4+ Hypoxia 60% DPP4+, p=.005). However, DPP4 activity on lineage- bone marrow harvested in hypoxia showed a 2 fold decrease (p=.005) compared to lineage- cells harvested in air. Interestingly, this increase in the number of DPP4+ cells in hypoxia is not recapitulated when mouse BM is harvested in the presence a Cyclosporin A, a cylophilin D inhibitor, (even though the increase in numbers of LT-HSC is preserved similarly to that in hypoxia) suggesting an alternative mechanism for modulation of DPP4 other than inhibition of mitochondrial ROS/MPTP. Unexpectedly, LT-HSC ROS levels (both mitochondrial and total) were not diminished in groups with decreased DPP4 activity (DPA or DPP4 K/O) harvested in air despite the blunting of EPHOSS leading to maintenance of the phenotypic LT-HSC increase over air harvest alone. These data suggest that pathways in addition to ROS, such as DPP4 expression/activity, may be influencing LT-HSC function after, and sensitivity to, EPHOSS as well as being modulated by EPHOSS. Further investigation of these collaborative pathways may facilitate increased HSC collections to enhance HSC transplantation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Low 5-year health care burden after umbilical cord blood transplantation

2021 ◽  
Vol 5 (3) ◽  
pp. 853-860
Author(s):  
Jesus Garcia Garcia ◽  
Sonya Grillo ◽  
Qing Cao ◽  
Claudio G. Brunstein ◽  
Mukta Arora ◽  
...  
Keyword(s):  
Health Care ◽  
Stem Cells ◽  
Bone Marrow ◽  
Umbilical Cord Blood ◽  
Peripheral Blood ◽  
Peripheral Blood Stem Cells ◽  
Care Burden ◽  
Health Care Burden ◽  
Blood Stem Cells

Abstract Recipients of allogeneic hematopoietic cell transplantation (HCT) experience a substantial health care burden, with potentially differing patterns of long-term health care requirements using peripheral blood stem cells, bone marrow, and umbilical cord blood (UCB) grafts. We analyzed data from 1077 consecutive adult allogeneic HCT recipients who underwent transplant at the University of Minnesota between 2000 and 2016. To estimate health care burden over time, we compared the number of visits, laboratory studies, medications, and relative value units billed. Health care elements were analyzed both individually and together (ie, total health care elements used per patient days into a density composite score). UCB had the lowest density health care burden composite score from the time of transplant through year 5 (median score 64.0 vs 70.5 for peripheral blood stem cells and 88.0 for bone marrow; P &lt; .01). In multivariate analysis of health care burden between years 1 and 5, recipients of either bone marrow (odds ratio [OR] 0.49 [95% confidence interval (CI) 0.29-0.84]) or peripheral blood stem cells (OR 0.49 [95% CI 0.36-0.67]) were half as likely to experience low health care burden compared with UCB. Adult recipients of UCB have a lower long-term health care burden compared with other graft sources, possibly reflecting a better quality of life.

Cytokine-Mediated Expansion of 5-FU Resistant Peripheral Blood Stem Cells and Bone Marrow: Self-Renewal and Commitment Capacity*

1994 ◽  
Vol 3 (2) ◽  
pp. 135-139
Author(s):  
ALISON RICE ◽  
JEAN-MICHEL BOIRON ◽  
CAROLINE BARBOT ◽  
MARYSE DUPOUY ◽  
NADINE DUBSOC-MARCHENAY ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Peripheral Blood ◽  
Peripheral Blood Stem Cells ◽  
Self Renewal ◽  
Blood Stem Cells

Automated washing of long-term cryopreserved peripheral blood stem cells promotes cell viability and preserves CD34+ cell numbers

2018 ◽  
Vol 53 (9) ◽  
pp. 1225-1227
Author(s):  
Fatima Aerts-Kaya ◽  
Gül Koca ◽  
Parisa Sharafi ◽  
Funda Çakmak Sayla ◽  
Duygu Uçkan-Çetinkaya ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cell Viability ◽  
Peripheral Blood ◽  
Peripheral Blood Stem Cells ◽  
Cell Numbers ◽  
Blood Stem Cells

scholarly journals Hematopoietic stem cells in the blood after stem cell factor and interleukin-11 administration: evidence for different mechanisms of mobilization

Blood ◽  
1995 ◽  
Vol 86 (12) ◽  
pp. 4674-4680 ◽  
Author(s):  
P Mauch ◽  
C Lamont ◽  
TY Neben ◽  
C Quinto ◽  
SJ Goldman ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Stem Cell Factor ◽  
Cytotoxic Agents ◽  
Peripheral Blood Stem Cells ◽  
Hematopoietic Stem ◽  
Blood Stem Cells ◽  
Interleukin 11

Peripheral blood stem cells and progenitor cells, collected during recovery from exposure to cytotoxic agents or after cytokine administration, are being increasingly used in clinical bone marrow transplantation. To determine factors important for mobilization of both primitive stem cells and progenitor cells to the blood, we studied the blood and splenic and marrow compartments of intact and splenectomized mice after administration of recombinant human interleukin-11 (rhlL-11), recombinant rat stem cell factor (rrSCF), and IL-11 + SCF. IL-11 administration increased the number of spleen colony- forming units (CFU-S) in both the spleen and blood, but did not increase blood long-term marrow-repopulating ability (LTRA) in intact or splenectomized mice. SCF administration increased the number of CFU- S in both the spleen and blood and did not increase the blood or splenic LTRA of intact mice, but did increase blood LTRA to normal marrow levels in splenectomized mice. The combination of lL-11 + SCF syngeristically enhanced mobilization of long-term marrow-repopulating cells from the marrow to the spleen of intact mice and from the marrow to the blood of splenectomized mice. These data, combined with those of prior studies showing granulocyte colony-stimulating factor mobilization of long-term marrow repopulating cells from the marrow to the blood of mice with intact spleens, suggest different cytokine- induced pathways for mobilization of primitive stem cells.

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