Role Of Cellular Therapies Research Articles

Viral infection in hematopoietic stem cell transplantation: an International Society for Cell & Gene Therapy Stem Cell Engineering Committee review on the role of cellular therapy in prevention and treatment

Despite recent advances in the field of HSCT, viral infections remain a frequent causeof morbidity and mortality among HSCT recipients. Adoptive transfer of viral specific T cells has been successfully used both as prophylaxis and treatment of viral infections in immunocompromised HSCT recipients. Increasingly, precise risk stratification of HSCT recipients with infectious complications should incorporate not only pretransplant clinical criteria, but milestones of immune reconstitution as well. These factors can better identify those at highest risk of morbidity and mortality and identify a population of HSCT recipients in whom adoptive therapy with viral specific T cells should be considered for either prophylaxis or second line treatment early after inadequate response to first line antiviral therapy. Broadening these approaches to improve outcomes for transplant recipients in countries with limited resources is a major challenge. While the principles of risk stratification can be applied, early detection of viral reactivation as well as treatment is challenging in regions where commercial PCR assays and antiviral agents are not readily available.

Management of Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma in the Era of Targeted Therapies.

The treatment landscape for relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has changed substantially over the past decade and continues to evolve. Despite the emergence of targeted therapies that are well tolerated and prolong survival, the disease remains incurable and relapse is common particularly in individuals with high-risk features. Herein, we review the key literature about the current options for relapsed disease and explore the emerging role of cellular therapies. Clinical trials have established the role of Bruton tyrosine kinase inhibitors, selective BCL-2 inhibition, and anti-CD20 monoclonal antibodies as treatment options for CLL/SLL. The role of chimeric antigen receptor T cells has shown promise in individuals with CLL/SLL in early phase clinical trials. Novel therapeutic approaches with targeted therapies have redefined the management of CLL/SLL in both the front-line and relapsed/refractory settings. Optimal management in terms of sequencing or combining therapies, especially in individuals with high-risk features, remains a challenge. The emerging role of cellular therapies has the potential to build upon and further improve the current treatment paradigm.

New Progress of Adipose-derived Stem Cells in the Therapy of Hypertrophic Scars.

Burns are a global public health issue of great concern. The formation of scars after burns and physical dysfunction of patients remain major challenges in the treatment of scars. Regenerative medicine based on cell therapy has become a hot topic in this century. Adipose-derived stem cells (ADSCs) play an important role in cellular therapy and have become a promising source of regenerative medicine and wound repair transplantation. However, the anti-scarring mechanism of ADSCs is still unclear yet. With the widespread application of ADSCs in medical, we firmly believe that it will bring great benefits to patients with hypertrophic scars.

Peripheral Blood Mononuclear Cells Therapy for Treatment of Lower Limb Ischemia in Diabetic Patients: A Single-Center Experience

The aim of this study is to analyze the effects of peripheral blood mononuclear cells (PBMNCs) therapy in diabetic patients with critical limb ischemia (CLI), with particular regard to its application, as adjuvant therapy in patients underwent endovascular revascularization. Fifty diabetic patients affected by CLI were enrolled. All patients underwent PBMNCs therapy. Thirty-two patients underwent PBMNCs therapy associated with endovascular revascularization (adjuvant therapy group). In 18 patients, who were considered nonrevascularizable or underwent unsuccessful revascularization, regenerative therapy with PBMNCs was performed as the therapeutic choice (PBMNCs therapy group). The median follow-up period was 10months. The baseline and end point results in adjuvant group were as follows. The mean transcutaneous partial pressure of oxygen (TcPO2) improved from 25±9.2mmHg to 45.6±19.1mmHg (P<0.001), and visual analogue scale (VAS) score means decreased from 8.6±2.1 to 3.8±3.5 (P=0.001). In PBMNCs therapy group, the mean TcPO2 improved from 16.2±7.2mmHg to 23.5±8.4mmHg (P<0.001), and VAS score means decreased from 9±1.1 to 4.1±3.3 (P=0.001). Major amputation was observed in 3 cases (9.4%), both in adjuvant therapy group and in PBMNCs therapy one (16.7%) (P=0.6). The role of cellular therapy with PBMNCs is decisive in the patients that are not susceptible to revascularization. In diabetic patients with CLI and healing resistant ulcers, the adjuvant PBMNCs therapy could represent a valid therapeutic option.

Isolation, molecular characterization, and in vitro differentiation of bovine Wharton jelly–derived multipotent mesenchymal cells

Extrafetal tissues are a noncontroversial and inexhaustible source of mesenchymal stem cells that can be harvested noninvasively at low cost. In the veterinary field, as in man, stem cells derived from extrafetal tissues express plasticity, reduced immunogenicity, and have high anti-inflammatory potential making them promising candidates for treatment of many diseases. Umbilical cord mesenchymal cells have been isolated and characterized in different species and have recently been investigated as potential candidates in regenerative medicine. In this study, cells derived from bovine Wharton jelly (WJ) were isolated for the first time by enzymatic methods, frozen/thawed, cultivated for at least 10 passages, and characterized. Wharton jelly–derived cells readily attached to plastic culture dishes displaying typical fibroblast-like morphology and, although their proliferative capacity decreased to the seventh passage, these cells showed a mean doubling time of 34.55 ± 6.33 hours and a mean frequency of one colony-forming unit fibroblast like for every 221.68 plated cells. The results of molecular biology studies and flow cytometry analyses revealed that WJ-derived cells showed the typical antigen profile of mesenchymal stem cells and were positive for CD29, CD44, CD105, CD166, Oct-4, and c-Myc. They were negative for CD34 and CD14. Remarkably, WJ-derived cells showed differentiation ability. After culture in induced media, WJ-derived cells were able to differentiate into osteogenic, adipogenic, chondrogenic, and neurogenic lines as shown by positive staining and expression of specific markers. On polymerase chain reaction analysis, these cells were negative for MHC-II and positive for MHC-I, thus reinforcing the role of extrafetal tissue as an allogenic source for bovine cell–based therapies. These results provide evidence that bovine WJ-derived cells may have the potential to differentiate to repair damaged tissues and reinforce the importance of extrafetal tissues as stem cell sources in veterinary regenerative medicine. A more detailed evaluation of their immunologic properties is necessary to better understand their potential role in cellular therapy.

Multilineage Potential Research of Bovine Amniotic Fluid Mesenchymal Stem Cells

The use of amnion and amniotic fluid (AF) are abundant sources of mesenchymal stem cells (MSCs) that can be harvested at low cost and do not pose ethical conflicts. In human and veterinary research, stem cells derived from these tissues are promising candidates for disease treatment, specifically for their plasticity, their reduced immunogenicity, and high anti-inflammatory potential. This work aimed to obtain and characterize bovine amniotic fluid mesenchymal stem cells (AFMSC). The bovine AF from the amniotic cavity of pregnant gilts in the early stages of gestation (3- and 4-m-old bovine embryos) was collected. AFMSCs exhibit a fibroblastic-like morphology only starting from the fourth passage, being heterogeneous during the primary culture. Immunofluorescence results showed that AFMSCs were positive for β-integrin, CD44, CD73 and CD166, but negative for CD34, CD45. Meanwhile, AFMSCs expressed ES cell markers, such as Oct4, and when appropriately induced, are capable of differentiating into ectodermal and mesodermal lineages. This study reinforces the emerging importance of these cells as ideal tools in veterinary medicine; future studies aimed at a deeper evaluation of their immunological properties will allow a better understanding of their role in cellular therapy.

Mesenchymal stem cells from amnion and amniotic fluid in the bovine

Amnion and amniotic fluid (AF) are noncontroversial and inexhaustible sources of mesenchymal stem cells (MSCs) that can be harvested noninvasively at low cost. As in humans, also in veterinary field, presumptive stem cells derived from these tissues reveal as promising candidates for disease treatment, specifically for their plasticity, their reduced immunogenicity, and high anti-inflammatory potential. The aim of this work is to obtain and characterize, for the first time in bovine species, presumptive MSCs from the epithelial portion of the amnion (AECs) and from the AF (AF-MSCs) to be used for clinical applications. AECs display a polygonal morphology, whereas AF-MSCs exhibit a fibroblastic-like morphology only starting from the second passage, being heterogeneous during the primary culture. For both lines, the proliferative ability has been found constant over the ten passages studied and AECs show a statistically lower (P<0.05) doubling time with respect to AF-MSCs. AECs express MSC-specific markers (ITGB1 (CD29), CD44, ALCAM (CD166), ENG (CD105), and NT5E (CD73)) from P1 to P3; in AF-MSCs, only ITGB1, CD44, and ALCAM mRNAs are detected; NT5E is expressed from P2 and ENG has not been found at any passage. AF-MSCs and AECs are positive for the pluripotent markers (POU5F1 (OCT4) and MYC (c-Myc)) and lack of the hematopoietic markers. When appropriately induced, both cell lines are capable of differentiating into ectodermal and mesodermal lineages. This study contributes to reinforce the emerging importance of these cells as ideal tools in veterinary medicine. A deeper evaluation of the immunological properties needs to be performed in order to better understand their role in cellular therapy.

Immunomodulation by Multipotent Mesenchymal Stromal Cells

Multipotent mesenchymal stromal cells (MSC) are currently under intense investigation to determine their role in cellular therapy. They are a rare subset of cells, but are easy to isolate and possess an extensive proliferative potential. MSC differentiate into cell types of mesenchymal and nonmesenchymal lineages, providing a promising tool for tissue repair. Studies in vitro have shown that they do not induce an immune response and inhibit cells of the immune system that are involved in alloantigen recognition and elimination. In animal models, MSC appear to have anti-inflammatory effects, which has also been observed in patients suffering from acute graft-versus-host disease. The unique properties of MSC suggest emerging roles for them in cell therapy and in the treatment of immunomediated diseases.

Progenitor Cell Therapy of Ischemic Heart Disease: The New Frontier

The discovery of circulating cells capable of differentiating into vascular structures (endothelial progenitor cells) has both altered our understanding of the pathophysiology of atherosclerosis and offered the possibility of using nature's reparative mechanisms to accelerate vascular restoration and regeneration. Epidemiologic studies indicate a correlation between cardiac risk factors, the presence of coronary disease and the numbers and function of endothelial progenitor cells. Preclinical animal models have demonstrated the therapeutic potential of cellular therapies for repair of ischemic myocardial damage. Several human trials investigating either the use of progenitor cells derived from bone marrow or peripheral blood, or pharmacologic therapies aimed at increasing mobilization of such cells for the treatment of ischemic heart disease, are currently underway. Some basic tenets of progenitor cell biology, key preclinical results suggesting the utility of this therapy, and the strengths and limitations of current human trials are briefly summarized, and the role of cellular therapies, today and in the future, are explored.

Ex vivo manipulation of cell subsets for cell therapies.

Large-scale cell separation and ex vivo expansion technologies will form the basis for development of new cellular products for the treatment of cancer and fatal viral diseases. The cell subsets that are likely to play a significant role in cellular therapy include hematopoietic stem cells, platelet and granulocyte precursors, cytotoxic lymphocytes, and genetically modified hematopoietic or lymphoid precursors. Cell enrichment techniques are required to eliminate tumor cells from autologous stem cell grafts and to reduce the size of culture systems required for expansion or gene transfection. The consumption of expensive culture components such as cytokines and serum may be reduced by the use of perfusion bioreactor devices. Methods that have been developed for the production of cell subsets for cellular therapy are reviewed.