Dynamics Of Cell Subpopulations Research Articles

Pre-Transplant Frequencies of FoxP3+CD25+ in CD3+CD8+ T Cells as Potential Predictors for CMV in CMV-Intermediate Risk Kidney Transplant Recipients.

Cytomegalovirus (CMV) infection detrimentally influences graft survival in kidney transplant recipients, with the risk primarily determined by recipient and donor serostatus. However, recipient CD8+ T cells play a crucial role in CMV control. The optimal preventive strategy (prophylaxis vs. pre-emptive treatment), particularly for seropositive (intermediate risk) recipients, remains uncertain. We investigated CD8+ T cell subpopulation dynamics and CMV occurrence (DNAemia ≥ 100IU/mL) in 65 kidney transplant recipients, collecting peripheral blood mononuclear cells before (T1) and 1year after transplantation (T2). Comparing the two timepoints, we found an increase in granulocyte, monocyte and CD3+CD8+ T cells numbers, while FoxP3+CD25+, LAG-3+ and PD-1+ frequencies were reduced at T2. CMV DNAemia occurred in 33 recipients (55.8%) during the first year. Intermediate risk patients were disproportionally affected by posttransplant CMV (N = 29/45, 64.4%). Intermediate risk recipients developing CMV after transplantation exhibited lower leukocyte, monocyte, and granulocyte counts and higher FoxP3+CD25+ frequencies in CD3+CD8+ T cells pre-transplantation compared to patients staying CMV negative. Pre-transplant FoxP3+CD25+ in CD3+CD8+ T cells had the best discriminatory potential for CMV infection prediction within the first year after transplantation (AUC: 0.746). The FoxP3+CD25+ CD3+CD8+ T cell subset may aid in selecting intermediate risk kidney transplant recipients for CMV prophylaxis.

CD_99 G1 neutrophils modulate osteogenic differentiation of mesenchymal stem cells in the pathological process of ankylosing spondylitis

ObjectivesThis study aimed to identify the types and heterogeneity of cells within the spinal enthesis and investigate the underlying mechanisms of osteogenesis.MethodsSingle-cell RNA sequencing was used to identify cell populations...

Modelling of killer T-cell and cancer cell subpopulation dynamics under immuno- and chemotherapies

Each patient’s cancer has a unique molecular makeup, often comprised of distinct cancer cell subpopulations. Improved understanding of dynamic processes between cancer cell populations is therefore critical for making treatment more effective and personalized. It has been shown that immunotherapy increases the survival of melanoma patients. However, there remain critical open questions, such as timing and duration of immunotherapy and its added benefits when combined with other types of treatments. We introduce a model for the dynamics of active killer T-cells and cancer cell subpopulations. Rather than defining the cancer cell populations based on their genetic makeup alone, we consider also other, non-genetic differences that make the cell populations either sensitive or resistant to a therapy. Using the model, we make predictions of possible outcomes of the various treatment strategies in virtual melanoma patients, providing hypotheses regarding therapeutic efficacy and side-effects. It is shown, for instance, that starting immunotherapy with a denser treatment schedule may enable changing to a sparser schedule later during the treatment. Furthermore, combination of targeted and immunotherapy results in a better treatment effect, compared to mono-immunotherapy, and a stable disease can be reached with a patient-tailored combination. These results offer better understanding of the competition between T-cells and cancer cells, toward personalized immunotherapy regimens.

Abstract B62: Intratumoral genetic heterogeneity in rectal cancer and response to neoadjuvant chemoradiotherapy

Abstract Response to neoadjuvant chemoradiotherapy (nCRT) varies substantially among patients with locally advanced rectal cancer, but key determinants of treatment response are not fully understood. Intratumoral genetic heterogeneity (ITGH) is a common feature of solid tumors and has been proposed to drive disease progression and treatment response. Others and we have recently demonstrated that primary nontreated rectal tumors exhibit significant ITGH, but the effect of nCRT in shaping the clonal architecture of rectal cancer has not yet been addressed. In the present work, we further expanded the analysis of ITGH in rectal cancer by analyzing whole-exome sequencing (WES) and clinical data from 79 primary nontreated rectal cancers obtained from The Cancer Genome Atlas. We show that primary rectal tumors exhibit a remarkable variability in the degree of ITH. We also analyzed the effect of nCRT on ITGH and monitored tumor cell subpopulation dynamics after treatment through WES of paired tumor samples collected at diagnosis (pretreatment) and at surgery following nCRT (post-treatment) from seven patients. We show that treatment exposure does not introduce novel somatic mutations or significantly alter tissue genetic heterogeneity. Instead, nCRT acts as a potent selective pressure, shaping the mutational landscape of rectal tumors and allowing the selection and expansion of tumor cell subpopulations, which are more prone to resist nCRT. Our results shed light on the highly heterogeneous and dynamic mutational landscape of rectal tumors and indicate that ITGH may directly affect response to nCRT. Citation Format: Cibele Masotti, Fabiana Bettoni, Bruna R. Correa, Angelita Habr-Gama, Joaquim Gama-Rodrigues, Maria Viana, Bruna B. Vailati, Guilherme P. Sao Juliao, Laura M. Fernandez, Pedro A. F. Galante, Rodrigo O. Perez, Anamaria A. Camargo. Intratumoral genetic heterogeneity in rectal cancer and response to neoadjuvant chemoradiotherapy [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B62.

Computational modeling of megakaryocytic differentiation of umbilical cord blood-derived stem/progenitor cells

Abstract Quantifying the effect of exogenous parameters regulating megakaryopoiesis would enhance the design of robust and efficient protocols to produce platelets. We developed a computational model based on time-dependent ordinary differential equations (ODEs) which decoupled expansion and differentiation kinetics of cells using a subpopulation dynamic model. The model described umbilical cord blood (UCB)-derived cell's behavior in response to the external stimuli during expansion and megakaryocytic differentiation ex vivo. We observed that the rate of expansion of Mk progenitors and production of mature Mks were higher when TPO was included in the expansion stage and cytokines were added during differentiation stage. Our computational approach suggests that the Mk progenitors were an important intermediate population that their dynamic should be optimized in order to establish an efficient protocol. This model provides important insights into dynamics of cell subpopulations during megakaryopoiesis process and could potentially contribute toward the rational design of cell-based therapy bioprocesses.

Aging disrupts cell subpopulation dynamics and diminishes the function of mesenchymal stem cells.

Advanced age is associated with an increased risk of vascular morbidity, attributable in part to impairments in new blood vessel formation. Mesenchymal stem cells (MSCs) have previously been shown to play an important role in neovascularization and deficiencies in these cells have been described in aged patients. Here we utilize single cell transcriptional analysis to determine the effect of aging on MSC population dynamics. We identify an age-related depletion of a subpopulation of MSCs characterized by a pro-vascular transcriptional profile. Supporting this finding, we demonstrate that aged MSCs are also significantly compromised in their ability to support vascular network formation in vitro and in vivo. Finally, aged MSCs are unable to rescue age-associated impairments in cutaneous wound healing. Taken together, these data suggest that age-related changes in MSC population dynamics result in impaired therapeutic potential of aged progenitor cells. These findings have critical implications for therapeutic cell source decisions (autologous versus allogeneic) and indicate the necessity of strategies to improve functionality of aged MSCs.

Reduced Regenerative Capacity of Aged Adipose Derived Stem Cells is Caused by Alterations of Cell Subpopulation Dynamics

Duscher, Dominik MD; Rennert, Robert C. MD; Januszyk, Michael MD, MS; Maan, Zeshaan N. MBBS, MS, MRCS; Whittam, Alexander J. BA; Hu, Michael S. MD, MPH, MS; Walmsley, Graham G. BA; Atashroo, David MD; Longaker, Michael T. MD, MBA, FACS; Gurtner, Geoffrey C. MD, FACS Author Information

Aorta Transplantation in Man: Clinical and Immunological Studies

Aortic transplantation has progressively gained interest over the last few years and it is becoming a first choice indication in the substitution of infected prostheses. The most frequent complication in long-term vascular outcome (wall thickening, aneurysmatic dilation, stenosis), may occur through an immunological mechanism. In this study we investigated nine recipients, aged 48 to 65 years, of aorta segment replacement for anti-HLA antibody production (specificity and Ig class), CD3-CD4-CD8 T cell subpopulation dynamics and aorta wall thickness. Mismatch-specific IgG antibodies to HLA class I and HLA class II antingens were detected 1, 3 and 6 months after transplantation and persisted at a high concentration for at least 1 year. Furthermore, the absolute number of CD3, CD4 and CD8 positive lymphocytes increased progressively after aorta allograft. Tomography scanning showed a progressive thickness of the aorta wall. We can speculate that these anti-HLA antibodies in the recipients have the potential to harm the implant; therefore, aorta allograft should involve the induction of immunological tolerance by appropriate immunosuppressants.

Mismatch-specific anti-HLA antibody production following aorta transplants.

In this study, we have investigated the nature and magnitude of the immunological response after implantation of human aortic segments. Five recipients of aortic segment replacement were studied for anti-HLA antibody production (specificity and Ig class), CD3, CD4, and CD8 T cell subpopulation dynamics, and aortic wall thickness. Mismatch-specific IgG antibodies to HLA class I and HLA class II antigens were first detected 1-3 months after implantation and persisted in high concentrations for at least 1 year. Computer tomography scanning showed a progressive thickness of the aortic wall. Also the absolute number of CD3, CD4, and CD8 positive lymphocytes increased progressively after implantation. In conclusion, as was observed earlier for heart valve allografts, human implanted aortic segments induce a strong anti-HLA antibody response in recipients. We speculate that these antibodies have the potential to harm the implant, for example, by having an impact on luminal narrowing.

Mismatch-specific anti-HLA antibody production following aorta transplants

Abstract In this study, we have investigated the nature and magnitude of the immunological response after implantation of human aortic segments. Five recipients of aortic segment replacement were studied for anti-HLA antibody production (specificity and Ig class), CD3, CD4, and CD8 T cell subpopulation dynamics, and aortic wall thickness. Mismatch-specific IgG antibodies to HLA class I and HLA class II antigens were first detected 1–3 months after implantation and persisted in high concentrations for at least 1 year. Computer tomography scanning showed a progressive thickness of the aortic wall. Also the absolute number of CD3, CD4, and CD8 positive lymphocytes increased progressively after implantation. In conclusion, as was observed earlier for heart valve allografts, human implanted aortic segments induce a strong anti-HLA antibody response in recipients. We speculate that these antibodies have the potential to harm the implant, for example, by having an impact on luminal narrowing.