scholarly journals Role of White Blood Cells in Blood- and Bone Marrow-Based Autologous Therapies

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
William King ◽  
Krista Toler ◽  
Jennifer Woodell-May
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Growth Factors ◽  
Blood Cells ◽  
Platelet Rich Plasma ◽  
White Blood Cells ◽  
Complex Mixture ◽  
Negative Results

There has been significant debate over the role of white blood cells (WBCs) in autologous therapies, with several groups suggesting that WBCs are purely inflammatory. Misconceptions in the practice of biologic orthopedics result in the simplified principle that platelets deliver growth factors, WBCs cause inflammation, and the singular value of bone marrow is the stem cells. The aim of this review is to address these common misconceptions which will enable better development of future orthopedic medical devices. WBC behavior is adaptive in nature and, depending on their environment, WBCs can hinder or induce healing. Successful tissue repair occurs when platelets arrive at a wound site, degranulate, and release growth factors and cytokines which, in turn, recruit WBCs to the damaged tissue. Therefore, a key role of even pure platelet-rich plasma is to recruit WBCs to a wound. Bone marrow contains a complex mixture of vascular cells, white blood cells present at much greater concentrations than in blood, and a small number of progenitor cells and stem cells. The negative results observed for WBC-containing autologous therapies in vitro have not translated to human clinical studies. With an enhanced understanding of the complex WBC biology, the next generation of biologics will be more specific, likely resulting in improved effectiveness.

The role of growth factors in self-renewal and differentiation of haemopoietic stem cells

1990 ◽  
Vol 327 (1239) ◽  
pp. 85-98 ◽  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Growth Factors ◽  
Stromal Cells ◽  
Cell Lineage ◽  
Self Renewal ◽  
Haemopoietic Stem Cells

Haemopoietic stem cells in vivo proliferate and develop in association with stromal cells of the bone marrow. Proliferation and differentiation of haemopoietic stem cells also occurs in vitro , either in association with stromal cells or in response to soluble growth factors. Many of the growth factors that promote growth and development of haemopoietic cells in vitro have now been molecularly cloned and purified to homogeneity and various techniques have been described that allow enrichment (to near homogeneity) of multipotential stem cells. This in turn, has facilitated studies at the mechanistic level regarding the role of such growth factors in self-renewal and differentiation of stem cells and their relevance in stromal-cell mediated haemopoiesis. Our studies have shown that at least some multipotential cells express receptors for most, if not all, of the haemopoietic cell growth factors already characterized and that to elicit a response, several growth factors often need to be present at the same time. Furthermore, lineage development reflects the stimuli to which the cells are exposed, that is, some stimuli promote differentiation and development of multipotential cells into multiple cell lineages, whereas others promote development of multipotential cells into only one cell lineage. We suggest that, in the bone marrow environment, the stromal cells produce or sequester different types of growth factors, leading to the formation of microenvironments that direct cells along certain lineages. Furthermore, a model system has been used to show the possibility that the self-renewal probability of multipotential cells can also be modulated by the range and concentrations of growth factors present in the environment. This suggests that discrete microenvironments, preferentially promoting self-renewal rather than differentiation of multipotential cells, may also be provided by marrow stromal cells and sequestered growth factors.

scholarly journals Effectiveness of Biologic Factors in Shoulder Disorders

2017 ◽  
Vol 11 (1) ◽  
pp. 163-182 ◽  
Author(s):  
Dimitrios Giotis ◽  
Ashkan Aryaei ◽  
Theofanis Vasilakakos ◽  
Nikolaos K. Paschos
Keyword(s):  
Stem Cells ◽  
Growth Factors ◽  
Clinical Studies ◽  
Platelet Rich Plasma ◽  
Repair Process ◽  
Poor Quality ◽  
Loss Of Function ◽  
Shoulder Disorders ◽  
Biologic Factors

Background:Shoulder pathology can cause significant pain, discomfort, and loss of function that all interfere with activities of daily living and may lead to poor quality of life. Primary osteoarthritis and rotator cuff diseases with its sequalae are the main culprits. Management of shoulder disorders using biological factors gained an increasing interest over the last years. This interest reveals the need of effective treatments for shoulder degenerative disorders, and highlights the importance of a comprehensive and detailed understanding of the rapidly increasing knowledge in the field.Methods:This study will describe most of the available biology-based strategies that have been recently developed, focusing on their effectiveness in animal and clinical studies.Results:Data fromin vitrowork will also be briefly presented; in order to further elucidate newly acquired knowledge regarding mechanisms of tissue degeneration and repair that would probably drive translational work in the next decade. The role of platelet rich-plasma, growth factors, stem cells and other alternative treatments will be described in an evidence-based approach, in an attempt to provide guidelines for their clinical application. Finally, certain challenges that biologic treatments face today will be described as an initiative for future strategies.Conclusion:The application of different growth factors and mesenchymal stem cells appears as promising approaches for enhancing biologic repair. However, data from clinical studies are still limited, and future studies need to improve understanding of the repair process in cellular and molecular level and evaluate the effectiveness of biologic factors in the management of shoulder disorders.

scholarly journals Rapid and sustained hematopoietic recovery in lethally irradiated mice transplanted with purified Thy-1.1lo Lin-Sca-1+ hematopoietic stem cells

Blood ◽  
1994 ◽  
Vol 83 (12) ◽  
pp. 3758-3779 ◽  
Author(s):  
N Uchida ◽  
HL Aguila ◽  
WH Fleming ◽  
L Jerabek ◽  
IL Weissman
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Blood Cells ◽  
Critical Role ◽  
White Blood Cells ◽  
Cell Types ◽  
Dose Dependence ◽  
Hematopoietic Stem ◽  
Hematopoietic Recovery

Abstract Hematopoietic stem cells (HSCs) are believed to play a critical role in the sustained repopulation of all blood cells after bone marrow transplantation (BMT). However, understanding the role of HSCs versus other hematopoietic cells in the quantitative reconstitution of various blood cell types has awaited methods to isolate HSCs. A candidate population of mouse HSCs, Thy-1.1lo Lin-Sca-1+ cells, was isolated several years ago and, recently, this population has been shown to be the only population of BM cells that contains HSCs in C57BL/Ka-Thy-1.1 mice. As few as 100 of these cells can radioprotect 95% to 100% of irradiated mice, resulting long-term multilineage reconstitution. In this study, we examined the reconstitution potential of irradiated mice transplanted with purified Thy-1.1lo Lin-Sca-1+ BM cells. Donor-derived peripheral blood (PB) white blood cells were detected as early as day 9 or 10 when 100 to 1,000 Thy-1.1lo Lin-Sca-1+ cells were used, with minor dose-dependent differences. The reappearance of platelets by day 14 and thereafter was also seen at all HSC doses (100 to 1,000 cells), with a slight dose-dependence. All studied HSC doses also allowed RBC levels to recover, although at the 100 cell dose a delay in hematocrit recovery was observed at day 14. When irradiated mice were transplanted with 500 Thy-1.1lo Lin-Sca-1+ cells compared with 1 x 10(6) BM cells (the equivalent amount of cells that contain 500 Thy-1.1lo Lin-Sca-1+ cells as well as progenitor and mature cells), very little difference in the kinetics of recovery of PB, white blood cells, platelets, and hematocrit was observed. Surprisingly, even when 200 Thy1.1lo Lin-Sca- 1+ cells were mixed with 4 x 10(5) Sca-1- BM cells in a competitive repopulation assay, most of the early (days 11 and 14) PB myeloid cells were derived from the HSC genotype, indicating the superiority of the Thy-1.1lo Lin-Sca-1+ cells over Sca-1- cells even in the early phases of myeloid reconstitution. Within the Thy-1.1lo Lin-Sca-1+ population, the Rhodamine 123 (Rh123)hi subset dominates in PB myeloid reconstitution at 10 to 14 days, only to be overtaken by the Rh123lo subset at 3 weeks and thereafter. These findings indicate that HSCs can account for the early phase of hematopoietic recovery, as well as sustained hematopoiesis, and raise questions about the role of non-HSC BM populations in the setting of BMT.

scholarly journals Circulating stem cells in mice treated with cyclophosphamide

Blood ◽  
1992 ◽  
Vol 80 (1) ◽  
pp. 264-269 ◽  
Author(s):  
CF Craddock ◽  
JF Apperley ◽  
EG Wright ◽  
LE Healy ◽  
CA Bennett ◽  
...  
Keyword(s):  
Stem Cells ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Cultured Cells ◽  
Autologous Transplantation ◽  
White Blood Cells ◽  
X Rays ◽  
Donor Cells ◽  
Macrophage Colony

Abstract Chemotherapy has been used clinically to mobilize hematopoietic progenitor cells into the peripheral blood so that they can be harvested for autologous transplantation. In humans, this is demonstrated by the presence of circulating granulocyte-macrophage colony-forming cells (CFU-GM) and CD34-positive cells, but it has not been possible to confirm the presence of marrow-repopulating stem cells. In this study, we treated mice with 200 mg/kg cyclophosphamide (CY) and measured the numbers of white blood cells, day 12 CFU-S (CFU- S12), and CFU-GM in the peripheral blood. There was a peak in the numbers of CFU-S12 and CFU-GM 8 days after treatment with cyclophosphamide. Peripheral blood cells taken at this time rescued lethally irradiated mice and engraftment of donor cells was confirmed after 140 days in sex mismatched recipients using a Y chromosome- specific probe. In vitro culture of the blood cells harvested after cyclophosphamide showed that they proliferated in suspension cultures for at least a year in the presence of interleukin-3. The cultured cells rapidly lost their abilities to rescue irradiated mice and to form colonies in vitro, but they did not become leukemic. Also, CY- treated mice were irradiated with a leukemogenic dose of x-rays to coincide with peak circulating cell numbers but these animals did not develop an excess of leukemias over mice given irradiation alone.

scholarly journals A review of the treatment landscape in paroxysmal nocturnal haemoglobinuria: where are we now and where are we going?

2020 ◽  
Vol 1 ◽  
pp. 263300402095934
Author(s):  
Morag Griffin ◽  
Richard Kelly ◽  
Alexandra Pike
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Life Expectancy ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Treatment Options ◽  
White Blood Cells ◽  
Paroxysmal Nocturnal Haemoglobinuria ◽  
Complement Cascade ◽  
Future Treatments

Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-orphan disease, which until 15 years ago had limited treatment options. Eculizumab, a monoclonal antibody that inhibits C5 in the terminal complement cascade, has revolutionised treatment for this disease, near normalising life expectancy and improving quality of life for patients. The treatment landscape of PNH is now evolving, with ravulizumab a second longer acting intravenous C5 inhibitor now licenced by the FDA and EMA. With different therapeutic targets in the complement cascade and difference modalities of treatment, including subcutaneous, oral and intravenous therapies being developed, increasing independence for patients and reducing healthcare requirements. This review discusses the current and future therapies for PNH. Lay summary Review of current and future treatments for patients with Paroxysmal Nocturnal Haemoglobinuria What is Paroxysmal Nocturnal Haemoglobinuria? Paroxysmal nocturnal haemoglobinuria (PNH) is a very rare disease. It arises from PNH stem cells in the bone marrow. In a normal bone marrow these are inactive; however, if there has been a problem in the bone marrow, the PNH stem cells can expand and make PNH red blood cells, white blood cells and platelets. The problem with these cells is that they lack the cell surface markers that usually protect them. Red blood cells are broken down in the circulation rather than the spleen, which gives rise to PNH symptoms such as abdominal pain, difficulty swallowing, erectile dysfunction and red or black urine (known as haemoglobinuria). The white blood cells and platelets are ‘stickier’ increasing the risk of blood clots. Previously life expectancy was reduced as there were limited treatment options available. What was the aim of this review? To provide an overview of current and future treatment options for PNH Which treatments are available? • Eculizumab is an treatment given through a vein (intravenous) every week for 5 weeks then every 2 weeks after this, and has been available for 13 years, improving life expectancy to near normal. • Ravulizumab is a newer intravenous treatment similar to eculizumab but is given every 8 weeks instead of every 2 weeks. In clinical studies it was comparable with eculizumab. • Future Treatments - There is new research looking at different methods of treatment delivery, including injections under the skin (subcutaneous) that patients can give themselves, treatments taken by mouth (oral) or a combination of an intravenous and oral treatment for those patients who are not optimally controlled on eculizumab or ravulizumab. What does this mean? PNH is now treatable. For years, the only drug available was eculizumab, but now different targets and drug trials are available. Ravulizumab is currently the only second licenced product available, in USA and Europe, there are other medications active in clinical trials. Why is this important? The benefit for patients, from treatment every 2 weeks to every 8 weeks is likely to be improved further with the development of these new treatments, providing patients with improved disease control and independence. As we move into an era of more patient-friendly treatment options, the PNH community both physicians and patients look forward to new developments as discussed in this article.

Differential Role for VLA-5 in Mobilization of Heamotopoieic Stem Cells Toward Peripheral Blood and Homing to Bone Marrow and Spleen.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2190-2190 ◽  
Author(s):  
Pieter K. Wierenga ◽  
Ellen Weersing ◽  
Bert Dontje ◽  
Gerald de Haan ◽  
Ronald P. van Os
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Hematopoietic Stem ◽  
Late Antigen ◽  
Cell Mobilization

Abstract Adhesion molecules have been implicated in the interactions of hematopoietic stem and progenitor cells with the bone marrow extracellular matrix and stromal cells. In this study we examined the role of very late antigen-5 (VLA-5) in the process of stem cell mobilization and homing after stem cell transplantation. In normal bone marrow (BM) from CBA/H mice 79±3 % of the cells in the lineage negative fraction express VLA-5. After mobilization with cyclophosphamide/G-CSF, the number of VLA-5 expressing cells in mobilized peripheral blood cells (MPB) decreases to 36±4%. The lineage negative fraction of MPB cells migrating in vitro towards SDF-1α (M-MPB) demonstrated a further decrease to 3±1% of VLA-5 expressing cells. These data are suggestive for a downregulation of VLA-5 on hematopoietic cells during mobilization. Next, MPB cells were labelled with PKH67-GL and transplanted in lethally irradiated recipients. Three hours after transplantation an increase in VLA-5 expressing cells was observed which remained stable until 24 hours post-transplant. When MPB cells were used the percentage PKH-67GL+ Lin− VLA-5+ cells increased from 36% to 88±4%. In the case of M-MPB cells the number increased from 3% to 33±5%. Although the increase might implicate an upregulation of VLA-5, we could not exclude selective homing of VLA-5+ cells as a possible explanation. Moreover, we determined the percentage of VLA-5 expressing cells immediately after transplantation in the peripheral blood of the recipients and were not able to observe any increase in VLA-5+ cells in the first three hours post-tranpslant. Finally, we separated the MPB cells in VLA-5+ and VLA-5− cells and plated these cells out in clonogenic assays for progenitor (CFU-GM) and stem cells (CAFC-day35). It could be demonstared that 98.8±0.5% of the progenitor cells and 99.4±0.7% of the stem cells were present in the VLA-5+ fraction. Hence, VLA-5 is not downregulated during the process of mobilization and the observed increase in VLA-5 expressing cells after transplantation is indeed caused by selective homing of VLA-5+ cells. To shed more light on the role of VLA-5 in the process of homing, BM and MPB cells were treated with an antibody to VLA-5. After VLA-5 blocking of MPB cells an inhibition of 59±7% in the homing of progenitor cells in bone marrow could be found, whereas homing of these subsets in the spleen of the recipients was only inhibited by 11±4%. For BM cells an inhibition of 60±12% in the bone marrow was observed. Homing of BM cells in the spleen was not affected at all after VLA-5 blocking. Based on these data we conclude that mobilization of hematopoietic progenitor/stem cells does not coincide with a downregulation of VLA-5. The observed increase in VLA-5 expressing cells after transplantation is caused by preferential homing of VLA-5+ cells. Homing of progenitor/stem cells to the bone marrow after transplantation apparantly requires adhesion interactions that can be inhibited by blocking VLA-5 expression. Homing to the spleen seems to be independent of VLA-5 expression. These data are indicative for different adhesive pathways in the process of homing to bone marrow or spleen.

Hedgehog Signaling Regulates HSC Proliferation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1390-1390
Author(s):  
Akil Merchant ◽  
Giselle Joseph ◽  
William Matsui
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Blood Cells ◽  
White Blood Cells ◽  
Wild Type ◽  
Serial Blood ◽  
Myeloid Progenitor ◽  
Hh Signaling ◽  
Progenitor Compartment

Abstract Hedgehog (Hh) signaling is essential for normal development and is dysregulated in many cancers. Hh signaling is active in normal bone marrow and the majority of acute myeloid leukemias, however, the precise role of Hh signaling and its positive effector Gli1 in normal or malignant hematopoiesis is not known. We have analyzed the bone marrow of Gli1 null mice to understand the role of this transcription factor in normal hematopoiesis in order to gain insight into its potential role in leukemia. Gli1 null mice develop normally and have normal peripheral blood counts but the bone marrow shows skewing of the c-Kit+Sca1+Lin-neg (KSL) progenitor compartment with increased CD34negKSL long-term HSC (LT-HSC) and decreased 34+KSL short-term HSC (ST-HSC). An analogous difference was observed in the c-Kit+Sca1negLinneg (KL) myeloid progenitor compartment with an increase in FcRγlowCD34+KL common myeloid progenitors (CMP) and decrease in the FcRγhighCD34+KL granulocyte monocyte progenitors (GMP). We speculated that these differences could be due to impaired cell cycle since both the ST-HSC and GMP are more proliferative than LT-HSC and CMP, respectively. Cell cycle analysis by DNA content and BrdU pulse labeling (100mg/kg IP 14 hours prior to analysis) revealed a marked decrease of proliferation in the LT-HSC, ST-HSC, CMP, and GMP compartments of Gli1 null mice. We supported this conclusion by demonstrating that the bone marrow of Gli1 null mice are relatively radio-resistant. Mice exposed to 400 cGy of total body irradiation followed with serial blood counts revealed less severe nadir, but delayed rebound of white blood cells in Gli1 null mice. We further hypothesized that although Gli1 appears to be dispensable for steady-state peripheral hematopoiesis, it might be necessary for rapid proliferation of progenitors needed during stressed hematopoiesis. In brain development, where Hh signaling is much better understood, active Hh signaling is critical for regulating proliferation of neural stem cells and Gli1 activity significantly increases after depletion of neural progenitors with chemotherapy (Bai et al., Development, 2002). To extend this observation to hematopoiesis, we treated Gli1 null mice and wild-type litter-mates with 5-fluorouracil (5-FU) at 100mg/kg and measured serial blood counts. Gli1 null mice had a delayed recovery of total white blood cells and neutrophil counts at 6 days after 5-FU, but this difference normalized by 20 days after treatment. To confirm that this difference was due to impaired proliferation and not increased sensitivity to 5-FU, we treated Gli1 null and wild-type mice with G-CSF (10mcg/kg/day) for three days to stimulate neutrophil proliferation. Confirming our hypothesis, we observed an attenuated neutrophil response in G-CSF stimulated Gli1 null mice. In summary, we have demonstrated that Gli1 loss leads to decreased HSC and myeloid progenitor proliferation, which has important functional consequences for stress hematopoiesis. These data suggest that abnormal Hh activity in leukemia may be important for driving the uncontrolled proliferation of cancer cells. Gli1 null mice were a kind gift from Alexandra Joyner, Memorial Sloan-Kettering Cancer Center

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