Alternative Immune-Mediated-Based Methods in the Aplastic Anemia Treatment

Acquired aplastic anemia (AA) is characterized by partial or total bone marrow (BM) destruction resulting in pancytopenia. Most of the acquired AA is the result of autoimmune condition the imbalance between T-regulatory cells (Treg), abnormal cytokines production and cytotoxic T cells activation, leading to the hematopoietic stem cells (HSCs) death. The first-line treatment is given by HSC transplant, but some patients did not respond to the treatment. Therefore, new technologies need to treat AA nonresponder patients. Studies are in progress to test the efficacy of stem cell-based therapeutic as mesenchymal stem cells (MSCs), which confer low immunogenicity and are reliable allogeneic transplants in refractory severe AA cases. Furthermore, MSCs comprise the BM stromal niche and have an important role in supporting hematopoiesis by secreting regulatory cytokines, providing stimulus to natural BM microenvironment. In addition, MSCs have immunomodulatory property and are candidates for efficient supporting AA therapy

Membrane-translocating peptides and toxins: from nature to bedside

Today, different functional classes of bioactive peptides and toxins isolated from diverse sources of living organisms are known. In medicine, these polypeptides present the potential to be used structurally unmodified or to serve as templates for molecular design of improved derivatives. Here, we refer to members of three classes of remarkable peptides and toxins that act at the cell membranes level and membrane trafficking systems: (i) the binary toxins (ii) the antimicrobial peptides and (iii) the cell penetrating peptides. Binary toxins have been genetically manipulated to generate specific immunotoxins, while antimicrobial peptides are in use as alternative agents against resistant microbes and tumor cells. Cell penetrating peptides have applications as diverse as cell transfection and transport of nanomaterials. Our group is dissecting the capacity of crotamine, a peptide from rattlesnake venom, to translocate cell membranes and use it as a delivery system in the transducing technology and molecular imaging.Atualmente, diferentes classes funcionais de peptídeos e toxinas biologicamente ativas isolados de diversos organismos são conhecidas. Em medicina, esses polipeptídios podem ser diretamente utilizados ou podem servir como modelos para a geração de moléculas derivadas. Aqui, nós fazemos referência a três classes de peptídeos e toxinas que agem sobre membranas celulares ou sobre sistemas de transporte por membranas: (i) toxinas binárias; (ii) peptídeos antimicrobianos; (iii) peptídeos penetradores de células. As toxinas binárias têm sido geneticamente manipuladas para gerar imunotoxinas específicas, enquanto os peptídeos antimicrobianos são usados como agentes alternativos contra células tumorais e microbianas resistentes. Os peptídeos penetradores de células têm aplicações que vão desde a transfecção celular quanto ao transporte intracelular de nanopartículas. Nosso grupo vem investigando a capacidade da crotamina, um peptídeo do veneno de cascavel, em translocar membranas celulares, bem como de utilizar a crotamina como sistema de transporte molecular e de análise de imagens.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de Pernambuco Departamento de BioquímicaClínica e Centro de Pesquisa em Reprodução Humana Roger AbdelmassihInstituto Butantan Laboratório de HerpetologiaUniversidade Federal de São Paulo (UNIFESP) Departamento de FarmacologiaInstituto Butantan Centro de Toxinologia AplicadaInstituto Butantan Laboratório de GenéticaCentro de Biotecnologia da AmazôniaInstituto de Pesquisas Energéticas e NuclearesUNIFESP, Depto. de FarmacologiaSciEL

Pluripotent Stem Cells to Model and Treat Huntington’s Disease

Stem cell therapies hold considerable promise for the treatment of neurodegenerative diseases. Pluripotent stem cells (PSCs) have been of particular clinical interest because of their ability to generate neuronal cells and to be used in animal models of neurodegenerative disease as well as for testing new drugs. Several PSCs isolated from humans and animals that carry the genotype of Huntington’s disease (HD) have been used in aforementioned studies. HD-PSCs obtained can produce in vitro neural progenitor cells (NPCs). These NPCs applied in HD models show several advantages: they engraft into the brain in animal models and differentiate into neuronal cells, thus promoting behavioral recovery and motor impairment. Although progress has been made using PSCs, additional tests should be done to overcome several limitations as, for example, tumorigenicity, before their clinical application. We focus this chapter on current knowledge regarding HD-PSC lines and their helpfulness as an in vitro model for basic research. Next, we discuss the advances of disease-free PSCs in preclinical HD models aiming to their potential application in patients. Additionally, we discuss their potential use as a test system for anti-HD drug screening by the pharmaceutical industry, especially considering HD patients’ welfare

Adipose Tissue-Derived Stem Cells and the Importance of Animal Model Standardization for Pre-Clinical Trials

ABSTRACTStem cells are undifferentiated cells and can self-renew and differentiate into various cell types, besides having immuno-modulating properties and paracrine effects in response to tissue injury, and may therefore treat injuries and diseases or even replace damaged or lost cells. Adipose tissue is an attractive source of adult stem cells, since the human body has a large reserve that is obtained in large amounts by minimally invasive methods. Interest in these cells has been increasing steadily due to their properties and possible applications in regenerative medicine and cell therapy. A large part of these investigations are focused on cardiovascular diseases, which are a leading cause of morbidity and mortality worldwide. Although in recent years treatments have advanced in cardiology, the development of new therapies to recover the damaged tissue still remains one of the main goals of cardiac research. However, to achieve effective results, in vivo and in vitro animal models for preclinical studies and consequently for application in humans must be standardized. The development of preclinical models in large animals requires the use of well-characterized animal cell lines, similar to human cells, and the use of the porcine model represents a great advantage for preclinical translational research

Brain-Derived Neurotrophic Factor and Stem Cell-Based Technologies in Huntington’s Disease Therapy

Neurodegenerative disorders, such as Huntington’s disease (HD), Alzheimer’s disease (AD), and Parkinson’s disease (PD), are characterized by changes in the levels and activities of neurotrophic factors (NTFs), such as brain-derived neurotrophic factor (BDNF). Gain-of-function and loss-of-function experiments demonstrate in fact the linkage between wild-type huntingtin (HTT) and gene transcription and intracellular transport of BDNF. In the present chapter, we will analyze the involvement of BDNF in HD and other neurodegenerative diseases. We will discuss the current BDNF technologies focusing on stem cell therapies that induce BDNF upregulation, for instance, the method of autologous mesenchymal stem cell (MSC) culturing in the presence of cocktail of BDNF inducers and factors (MSC/BDNF), genetic engineering of MSC and their use as a vector for BDNF gene delivery, and combined method of establishment of embryonic stem cell (ESC)-derived BDNF-overexpressing neural progenitors, which is still at the preclinical stage. Clinical trial that uses MSC/BDNF is already in course, while genetic engineering of MSC/BDNF is in perspective to treat adult and juvenile HD. The potential application of these technologies is beyond HD. Other neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases also can be further included in the list of clinical trials that use MSC/BDNF or even ESC/BDNF-overexpressing neural progenitors