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Production, Development, and Maturation of Red Blood Cells
Published in Ovide Arino, David E. Axelrod, Marek Kimmel, Mathematical population dynamics, 2020
Annette Grabosch, Henk J. A. M. Heijmans
Besides those morphological facts there is still a lot of uncertainty and speculation concerning how the regulation of this complex production system works. It is unquestioned that proteins play an important role in the regulation process. For red blood cell production, the protein erythropoietin seems to be of some importance. This influence has an obvious explanation from the following observation. A decreased number of red blood cells leads to a decreased amount of hemoglobin, thus to a decrease in the arterial oxygen tension. This stimulates the release of erythropoietin by the kidney. Finally, this protein causes an increased influx of red blood cells into the blood. Nevertheless, it seems not to be clear precisely what leads to the increased influx flow: a sudden release of nearly mature precursor cells, a higher division rate of stem cells, an increased flow from the stem cell compartment to the precursor cell compartment, a faster maturation velocity, a combination of these changes, or still another mechanism. A second protein that seems to be involved in the regulation of blood cell production is chalone, which is known to inhibit mitosis (see, e.g., Kirk et al., 1970) and appears to influence the dynamics (respectively, the production) of the stem cells (see, e.g., Kirk et al., 1970). A restricting factor for the maturation process seems to be the amount of iron available in the blood. This is clear by the fact that iron is one of the main constituents of hemoglobin. Similarly, there are some proteins and growth factors known to be of importance for the regulation of the other blood components. For example, in the myeloid cell line the protein granolopoietin and some less well known colony stimulating factors (CSFs) are involved. For the megakaryocyte line the protein thrombopoietin is of importance. The “natural” regulation mechanism for the different blood components is of course the destruction of blood cells with a cell-type specific rate and the production of new cells by the stem cells. But, as described above, there are many important steps in between which are responsible for the fine regulation. In a normally functioning (healthy) system, cell death does not seem to occur in the stem cell compartment or in the precursor cell stage, but it occurs naturally in the blood cell compartment. In the first two compartments, cell death may arise due to an artificial disturbance of the system. Nevertheless the physiological processes leading to exact regulation are more-or-less unknown. We get the schematical diagram of red blood cell production shown in Fig. 2.
Collection and Expansion of Stem Cells
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
In a study performed at the University of Colorado, 21 patients with high risk stage II, III, or IV breast cancer were treated with ex vivo expanded PBPC.107 All patients were mobilized with rhG-CSF (10 μg/kg/day) for 9 days and PBPC were harvested on days 5 through 9, with CD34+ cell selection preformed on the first four collections. The fifth collection was frozen unselected as a backup product. CD34+ selection was performed using the Isolex 300i. After selection, each product was frozen in liquid nitrogen. On day -10 of treatment, two PBPC products were thawed and placed into ex vivo expansion culture. The cells were diluted in Defined Media supplemented with 100 ng/ml each of rhSCF, rhMGDF and rhG-CSF to 20,000 cells per ml in 800 ml of media and transferred into teflon bags (American Fluoroceal). The bags were incubated at 37°C for 10 days in a 5% CO2 incubator. On day 0 of treatment the cultures were harvested using a cell washer (Cobe) and the media and growth factors removed with washing. Following ex vivo expansion of the CD34 selected cells, patients in cohort 1 (N=10) were reinfused with expanded cells on day 0 followed by unexpanded CD34+ cells. Patients in cohort 2 (N=10) received only ex vivo expanded cells and the unexpanded CD34+ cells were maintained frozen in liquid nitrogen as a backup source of hematopoietic cells. Transplantation of ex vivo expanded PBPC resulted in rapid engraftment of neutrophils (ANC>500/μl) with one patient engrafting on day 4 and a number of patients engrafting on days 5 and 6. The median time of neutrophil engraftment was day 6 in the first 15 patients. Historical controls had a median time to neutrophil engraftment of 9 days, with a range of 7 to 30 days. The patients in cohort 2 were transplanted with only expanded cells and all patients are alive and have maintained a durable graft at two years post-transplantation. No significant effect on platelet recovery was observed in any of the cohorts studied. These patients will be monitored long term to determine if expansion of the cells compromises long term engraftment. However, since the expanded cells were not marked by retroviral transduction, the contribution of endogenous hematopoietic recovery will be difficult to assess. Failure of the expanded cells to have an effect on platelet recovery may result from culture conditions that do not support platelet precursors. Alternatively, the expanded cells may require thrombopoietin (TPO) following transplantation to drive platelet production. These results demonstrate that infusion of expanded cells improves neutrophil engraftment, and suggest that this approach may be beneficial to reduce complications associated with neutropenia.
Investigation of novel sorafenib tosylate loaded biomaterial based nano-cochleates dispersion system for treatment of hepatocellular carcinoma
Published in Journal of Dispersion Science and Technology, 2021
Raj J. Ahiwale, Bothiraja Chellampillai, Atmaram P. Pawar
Values of the hematological parameters in Table 4 are discussed as follows. WBC count in DEN induced group, DEN + ST group, and DEN + STNCs group non-significantly roused as compared to the control group. The WBC rise may be due to the presence of cancer injury and extrahepatic metastasis.[63] Further, the treatment with chemotherapy also leads to Leukocytosis associated with thrombosis due to the initiation of chemotherapy.[64] The other possible reason for the rise in WBC may be due to infection. This may have caused the upregulation of the normal level of WBC. No abnormal changes were seen in lymphocytes and monocytes. Liver disease is accompanied by multiple hematological abnormalities. Low-level RBC in the DEN group and DEN + ST group as compared to the control group may be due to liver cirrhosis and liver damage.[65] In the DEN + STNCs group, the RBC level was low whilst it was closer to the normal range. Iron deficiency anemia is a frequent complication of advanced liver disease. Low level of HCT in the DEN group as compared to the control group, DEN + ST group, and DEN + STNCs group may be due to low iron level, a mineral that helps produce red blood cells.[66] This was evident from the low level of RBC. The MCV level in DEN induced group, DEN + ST group, and DEN + STNCs group are above normal range signals bigger size of RBCs, this may be due to low vitamin B12 or folate levels and liver disease.[67] MCH levels in DEN induced group and DEN + ST group were significantly higher than the control group, DEN + STNCs group levels though above the control group, however, are closer to normal level this delineates lipid carrier helped in keeping the liver damage low as compared to the pure drug-treated group and DEN control. High-level MCH is associated with liver disease and also related to low vitamin B12 or folate levels.[68] The hemoglobin level in all groups was normal however the MCHC levels are elevated in DEN induced group, DEN + ST group, and DEN + STNCs group as compared to the control group which represents fragile and destroyed RBC, leading to hemoglobin being present outside the RBCs. Platelet levels of DEN induced group, DEN + ST group, and DEN + STNCs group were elevated as compared to the control group. Liver tumor synthesizes thrombopoietin, a major factor in platelet production, therefore HCCs produce paraneoplastic thrombocytosis.[69] All DEN induced groups showed thrombocytosis. However, the severity was high in DEN induced group and DEN + ST group. The severity of thrombocytosis was low in the DEN + STNCs group, indicating enhanced antitumor action due to lipid carrier. The animals were only treated with ST and STNCs. Nevertheless, the results have shown enhanced functionality of STNCs, the animals need adjuvant therapy for restoring the MCV, MCH, MCHC, PLT, and WBC.