In vitro expansion of CD13+CD33+ dendritic cell precursors from multipotent progenitors is regulated by a discrete fas-mediated apoptotic schedule

Santiago‐Schwarz, Frances; Borrero, Michelle; Tucci, John; Palaia, Thomas; Carsons, Steven E.

doi:10.1002/jlb.62.4.493

Cited by 21 publications

(15 citation statements)

References 12 publications

(1 reference statement)

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“…The mean number of apoptotic cells ranged from 0.87 to 2.3% in all of the cultures, as assessed by microscopic analysis of propidium iodide-and Wright-stained cells (Ͼ500 cells per slide). These low levels of apoptosis are in agreement with steady-state levels previously observed in normal cells (25).…”

Section: Rasf Induces Ihsp70 Releasesupporting

confidence: 92%

Aberrant Extracellular and Dendritic Cell (DC) Surface Expression of Heat Shock Protein (hsp)70 in the Rheumatoid Joint: Possible Mechanisms of hsp/DC-Mediated Cross-Priming

Martin

Carsons

Kowalewski

et al. 2003

The Journal of Immunology

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We describe, in rheumatoid arthritis (RA), abnormalities in the expression and distribution of heat shock protein (hsp) and dendritic cells (DCs) that are conducive to cross-priming and DC cross-talk. As detected by ELISA, inducible (i)hsp70 was dramatically increased in RA synovial fluid (RASF) vs normal human and RA sera and osteoarthritis and gout synovial fluid. Immunoblot analysis of fresh RASF cells revealed marked increases in ihsp70 and activation of its transcription factor heat shock factor-1, compared with fresh normal peripheral blood cells. Flow cytometry and microscopy demonstrated high levels of ihsp70 on the surface of RASF myeloid DCs (but not normal myeloid DCs) that occurred concurrently with hspRs (CD91/CD14). ihsp70 present in RASF exhibited chaperoning potential, as indicated by the capture of ihsp70 present in RASF on the surface of normal DCs. Binding was partially competitively inhibited by excess α2-macroglobulin, indicating that hspRs in addition to CD91 participate in the capture process. These data indicate that ihsp70 may chaperone autologous Ags into immature RASF DCs via hspRs, and that cross-talk between DCs coexpressing hsp/hspRs reflects a disease process in RA. The induction of surface ihsp70 on normal cells after sublethal heat stress and the release of ihsp70 from normal DCs after inflammatory stress also suggest that the pattern of ihsp70 expression in RASF occurs in response to sustained stress.

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Section: Rasf Induces Ihsp70 Releasesupporting

confidence: 92%

Aberrant Extracellular and Dendritic Cell (DC) Surface Expression of Heat Shock Protein (hsp)70 in the Rheumatoid Joint: Possible Mechanisms of hsp/DC-Mediated Cross-Priming

Martin

Carsons

Kowalewski

et al. 2003

The Journal of Immunology

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“…ϩ cells, which is consistent with a myeloid DC (immature and mature) phenotype (30,41). Passage of SF MNCs over NW produced a nonadherent cell subset that lacked mature myeloid DCs (DR ϩ CD86 ϩ cells) and myeloid DC precursors, and that was enriched in myeloid progenitors (CD13…”

Section: Discussionsupporting

confidence: 60%

“…1A, right plots). The NW nonadherent SF FSC area (Table I) was particularly enriched in a myelodendritic cell-like progenitor compared with the SF MNC FSC area, as revealed by increases in CD115 (3-fold, p ϭ 0.01), decreases in CD14 and CD86 ( p Ͻ 0.01), and DR, CD13, and CD33 reactivity (13,41). Neither the RA SF MNCs nor the RA SF nonadherent cells expressed CD34, which is consistent with the lack of CD34 on hemopoietic cells in the RA joint (30).…”

Section: Cd13mentioning

confidence: 99%

Dendritic Cells (DCs) in Rheumatoid Arthritis (RA): Progenitor Cells and Soluble Factors Contained in RA Synovial Fluid Yield a Subset of Myeloid DCs That Preferentially Activate Th1 Inflammatory-Type Responses

Santiago‐Schwarz

Anand

Liu

et al. 2001

The Journal of Immunology

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116

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There is evidence that mature dendritic cells (DCs) present in the rheumatoid arthritis (RA) joint mediate immunopathology in RA. In this study, we indicate that early myeloid progenitors for DCs and DC growth factors existing in RA synovial fluid (SF) are also likely participants in the RA disease process. A fraction of cells lacking markers associated with mature DCs or DC precursors and enriched in CD34negative myeloid progenitors was isolated from RA SF. These cells proliferated extensively when cultured in vitro with cytokines that promote the growth of myeloid DCs (GM-CSF/TNF/stem cell factor/IL-4) and, to a lesser degree, when cultured with monocyte/granulocyte-restricted growth factors (M-CSF/GM-CSF). Mature DCs derived from RA SF progenitors with CD14-DC cytokines known to be prevalent in the inflamed RA joint (GM-CSF/TNF/stem cell factor/IL-13) were potent stimulators of allogeneic T cells and inflammatory-type Th1 responses and included CD14-DC subtypes. Cell-free RA SF facilitated DC maturation from myeloid progenitors, providing direct evidence that the inflamed RA joint environment instructs DC growth. Enhanced development of CD14-derived DCs was correlated with the presence of soluble TNFR (p55), raising the possibility that soluble TNFR also regulate CD14-derived DC growth in vivo. SF from patients with osteoarthritis contained neither myeloid DC progenitors nor DC growth factors. The existence of DC progenitors and myeloid DC growth factors in RA SF supports the concept that RA SF may be a reservoir for joint-associated DCs and reveals a compelling mechanism for the amplification and perpetuation of DC-driven responses in the RA joint, including inflammatory-type Th1 responses.

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“…Since supportive chemokines induce progenitor differentiation in these extended cultures, 34,35 we reasoned that differential sensitivity to apoptosis might be useful for depletion of the differentiated progeny. We used a CD34 + expansion protocol based on nicotinamide 28 and supplemented toxic doses of FasL (50 ng/mL) during the third week of culture, the period associated with largest quantitative expansion of cells.…”

Section: Resultsmentioning

confidence: 99%

“…Consistent with application of each one of the death ligands alone, combined exposure to FasL and TNF-α has no detrimental consequences, in contrast to negative effects in chemokine-supplemented cultures 29,30 that induce cell cycling and differentiation. 34,35 Both TNF receptors equally contribute to upregulation of Fas in UCB progenitors within several events mediated by receptor crosstalk. 37 Notably, joint exposure to TNF-α and FasL does not result in cumulative enrichment in progenitors, suggesting that nonprogenitor cells share redundant sensitivities to both receptors.…”

Section: Discussionmentioning

confidence: 99%

Negative selection by apoptosis enriches progenitors in naïve and expanded human umbilical cord blood grafts

Mizrahi

Ash

Peled

et al. 2014

Bone Marrow Transplant

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The influence of TNF-α and Fas-ligand (FasL) on viability and function was evaluated in fresh-and expanded-umbilical cord blood (UCB) cells. CD34 + progenitors and T cells display outstanding survival, whereas~30% and >50% B lymphocytes and myeloid cells undergo spontaneous apoptosis within 24 and 48 h, respectively. Although the impact of exposure to toxic doses of FasL and TNF-α was undetectable in measurements of apoptosis; removal of dead cells after 2 days of incubation with the ligands revealed a twofold increase in frequency of colony-forming cells (CFU). The sensitivity of progenitors to apoptosis was also unaffected by Fas cross-linking following TNF-induced upregulation of the receptor, increasing CFU frequency without impairing SCID repopulating cell (SRC) activity. Most significant enrichment in CD34 + progenitors and corresponding increase in CFU frequency were observed when FasL was applied during the final week of ex vivo expansion under the influence of nicotinamide, without impairing SRC activity. These data emphasize differential sensitivities of UCB progenitors and lineage-positive cells to apoptotic signaling mediated by the Fas and TNF receptors, which might be useful in improving the efficiency of ex vivo expansion and improving UCB cell engraftment.

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In vitro expansion of CD13+CD33+ dendritic cell precursors from multipotent progenitors is regulated by a discrete fas-mediated apoptotic schedule

Abstract: Abstract:We provide new information on how apoptosis regulates the expansion and survival of dendrit-

Cited by 21 publications

References 12 publications

Aberrant Extracellular and Dendritic Cell (DC) Surface Expression of Heat Shock Protein (hsp)70 in the Rheumatoid Joint: Possible Mechanisms of hsp/DC-Mediated Cross-Priming

Aberrant Extracellular and Dendritic Cell (DC) Surface Expression of Heat Shock Protein (hsp)70 in the Rheumatoid Joint: Possible Mechanisms of hsp/DC-Mediated Cross-Priming

Dendritic Cells (DCs) in Rheumatoid Arthritis (RA): Progenitor Cells and Soluble Factors Contained in RA Synovial Fluid Yield a Subset of Myeloid DCs That Preferentially Activate Th1 Inflammatory-Type Responses

Negative selection by apoptosis enriches progenitors in naïve and expanded human umbilical cord blood grafts

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