PubMed · 11388738
The source did not provide an abstract. Follow the original record for more information.
Explore connections, maps & timelines
C Piechaczek. CD133.. https://pubmed.ncbi.nlm.nih.gov/11388738/
Cite the original work for its findings. Save a collection to share your selection of sources.
KEEP EXPLORING
Pancreatic ductal adenocarcinoma (PDA) is among the deadliest malignancies, driven by metastatic progression and profound cellular heterogeneity. We previously identified glutathione S-transferase theta 1 (GSTT1) as a regulator of a slow-cycling, highly metastatic tumor cell population, suggesting that GSTT1High cells may possess stem-like properties. Here, we define the functional and molecular features of this subpopulation in metastatic PDA. Using a mCherry-tagged Gstt1 reporter system in metastatic murine PDAC cells, we enriched for Gstt1High cells and observed increased tumor sphere formation, accompanied by upregulation of stemness-associated genes including PROM1 (CD133) and activation of Wnt and FGF signaling pathways. In human PDA models, CD133HighGSTT1High cells exhibited enhanced tumor sphere initiation and expansion compared to other populations, defining a maximal stem-like state. Notably, sensitivity to FGFR inhibitors was observed only under tumor sphere conditions, highlighting a context-dependent therapeutic vulnerability. Mechanistically, FGFR3 expression correlated with GSTT1 and CD133 levels, and FGF signaling was required to sustain this state. GSTT1 knockdown reduced CD133 protein levels, impaired tumor sphere formation, and altered sensitivity to FGFR inhibition. These findings were largely recapitulated in patient-derived PDA organoids, where GSTT1 and PROM1 co-expression predicted increased tumor sphere formation and enhanced response to the multi-kinase inhibitor Nintedanib. Together, these results identify a GSTT1HighCD133High stem-like subpopulation in metastatic PDA and identify an FGFR-dependent signaling axis that sustains this state, representing a potential therapeutic vulnerability.
The hemopoietic stem cell (HSC) compartment encompasses cell subsets with heterogeneous proliferative and developmental potential. Numerous CD34(-) cell subsets that might reside at an earlier stage of differentiation than CD34(+) HSCs have been described and characterized within human umbilical cord blood (UCB). We identified a novel subpopulation of CD34(-)CD133(-)CD7(-)CD45(dim)lineage (lin)(-) HSCs contained within human UCB that were endowed with low but measurable extended long-term culture-initiating cell activity. Exposure of CD34(-)CD133(-)CD7(-)CD45(dim)lin(-) HSCs to stem cell factor preserved cell viability and was associated with the following: 1) concordant expression of the stem cell-associated Ags CD34 and CD133, 2) generation of CFU-granulocyte-macrophage, burst-forming unit erythroid, and megakaryocytic aggregates, 3) significant extended long-term culture-initiating cell activity, and 4) up-regulation of mRNA signals for myeloperoxidase. At variance with CD34(+)lin(-) cells, CD34(-)CD133(-)CD7(-)CD45(dim)lin(-) HSCs maintained with IL-15, but not with IL-2 or IL-7, proliferated vigorously and differentiated into a homogeneous population of CD7(+)CD45(bright)CD25(+)CD44(+) lymphoid progenitors with high expression of the T cell-associated transcription factor GATA-3. Although they harbored nonclonally rearranged TCRgamma genes, IL-15-primed CD34(-)CD133(-)CD7(-)CD45(dim)lin(-) HSCs failed to achieve full maturation, as manifested in their CD3(-)TCRalphabeta(-)gammadelta(-) phenotype. Conversely, culture on stromal cells supplemented with IL-15 was associated with the acquisition of phenotypic and functional features of NK cells. Collectively, CD34(-)CD133(-)CD7(-)CD45(dim)lin(-) HSCs from human UCB displayed an exquisite sensitivity to IL-15 and differentiated into lymphoid/NK cells. Whether the transplantation of CD34(-)lin(-) HSCs possessing T/NK cell differentiation potential may impact on immunological reconstitution and control of minimal residual disease after HSC transplantation for autoimmune or malignant diseases remains to be determined.
This report investigated in vivo turnover kinetics of marrow hematopoietic progenitors and precursors using a recently developed stable isotope-mass spectrometric technique (SIMST). Human subjects were administered a 2-day infusion of 6,6-[2H2]-glucose, a nontoxic stable isotope-labeled form of glucose, which becomes incorporated into DNA of all S-phase cells. The percent [2H2]-glucose incorporated into DNA in the form of [2H2]-deoxyadenosine (%[2H2]-dA enrichment) was determined by gas chromatography-mass spectrometry. The rate constant of replacement of unlabeled by labeled DNA strands (labeling kinetics) was used to calculate population turnover kinetics of CD34+ cells, CD133+ cells, and CD133-CD34+ cells. The observed mean replacement half-life (t1/2) was 2.6 days for CD34+ cells, 2.5 days for CD133-CD34+ cells, and 6.2 days for CD133+ cells. Results from the estimated rate constant of replacement of labeled by unlabeled DNA (delabeling kinetics) also demonstrated slower turnover rates for CD133+ cells than for CD133-CD34+ cells. Although there was a relatively rapid initial decrease in the %[2H2]-dA enrichment, low levels of labeled DNA persisted in CD34+ cells for at least 4 weeks. The results indicate the presence of subpopulations of CD34+ cells with relatively rapid turnover rates and subpopulations with a slower t1/2 of 28 days. Results also demonstrate that in vivo [2H2]-glucose-SIMST is sensitive enough to detect differences in turnover kinetics between erythroid and megakaryocyte lineage cells. These studies are the first to demonstrate the use of in vivo [2H2]-glucose-SIMST to measure in vivo turnover kinetics of subpopulations of CD34+ cells and precursors in healthy human subjects.