The mobilization and effect of endogenous bone marrow progenitor cells in diabetic wound healing

Diabetic patients suffer from impaired wound healing, characterized by only modest angiogenesis and cell proliferation. Stem cells may stimulate healing, but little is known about the kinetics of mobilization and function of bone marrow progenitor cells (BM-PCs) during diabetic wound repair. The objective of this study was to investigate the kinetics of BM-PC mobilization and their role during early diabetic wound repair in diabetic db/db mice. After wounding, circulating hematopoietic stem cells (Lin 12c-Kit+Sca-1+) stably increased in the periphery and lymphoid tissue of db/db mice compared to unwounded controls. Peripheral endothelial progenitor cells (CD34+VEGFR+) were 2.5- and 3.5-fold increased on days 6 and 10 after wounding, respectively. Targeting the CXCR4\u2013CXCL12 axis induced an increased release and engraftment of endogenous BM-PCs that was paralleled by an increased expression of CXCL12/SDF-1\u3b1 in the wounds. Increased levels of peripheral and engrafted BM-PCs corresponded to stimulated angiogenesis and cell proliferation, while the addition of an agonist (GM-CSF) or an antagonist (ACK2) did not further modulate wound healing. Macroscopic histological correlations showed that increased levels of stem cells corresponded to higher levels of wound reepithelialization. After wounding, a natural release of endogenous BMPCs was shown in diabetic mice, but only low levels of these cells homed in the healing tissue. Higher levels of CXCL12/SDF-1\u3b1 and circulating stem cells were required to enhance their engraftment and biological effects. Despite controversial data about the functional impairment of diabetic BM-PCs, in this model our data showed a residual capacity of these cells to trigger angiogenesis and cell proliferatio

Targeting the CXCR4-CXCL12 Axis Mobilizes Autologous Hematopoietic Stem Cells and Prolongs Islet Allograft Survival via Programmed Death Ligand 1

Antagonism of CXCR4 disrupts the interaction between the CXCR4 receptor on hematopoietic stem cells (HSCs) and the CXCL12 expressed by stromal cells in the bone marrow, which subsequently results in the shedding of HSCs to the periphery. Because of their profound immunomodulatory effects, HSCs have emerged as a promising therapeutic strategy for autoimmune disorders. We sought to investigate the immunomodulatory role of mobilized autologous HSCs, via target of the CXCR4-CXL12 axis, to promote engraftment of islet cell transplantation. Islets from BALB/c mice were transplanted beneath the kidney capsule of hyperglycemic C57BL/6 mice, and treatment of recipients with CXCR4 antagonist resulted in mobilization of HSCs and in prolongation of islet graft survival. Addition of rapamycin to anti-CXCR4 therapy further promoted HSC mobilization and islet allograft survival, inducing a robust and transferable host hyporesponsiveness, while administration of an ACK2 (anti-CD117) mAb halted CXCR4 antagonist-mediated HSC release and restored allograft rejection. Mobilized HSCs were shown to express high levels of the negative costimulatory molecule programmed death ligand 1 (PD-L1), and HSCs extracted from wild-type mice, but not from PD-L1 knockout mice, suppressed the in vitro alloimmune response. Moreover, HSC mobilization in PD-L1 knockout mice failed to prolong islet allograft survival. Targeting the CXCR4\u2013CXCL12 axis thus mobilizes autologous HSCs and promotes long-term survival of islet allografts via a PD-L1\u2013mediated mechanis

Investimento parental e desenvolvimento da criança Parental investment and child development

Segundo a teoria do investimento parental, seria esperada uma relação entre condições de criação da mãe e sua carreira reprodutiva e, por conseqüência, seus padrões de cuidado aos filhos, com repercussões no desenvolvimento das crianças. Esta pesquisa buscou verificar essas relações, em amostra de 37 mães e seus filhos entre um e quatro anos, de um bairro pobre de Salvador, Bahia. Foi investigada a história familiar e reprodutiva das mães, associada a resultados desenvolvimentais das crianças, medidos através das escalas Bayley e WIPPSI-R, em quatro avaliações realizadas ao longo de três anos. Foram encontradas correlações entre condições de criação da mãe e sua carreira reprodutiva subseqüente. Por sua vez, esses padrões mostraram-se modestamente relacionados ao desenvolvimento cognitivo de seus filhos, favorecendo as crianças cujas mães iniciaram sua vida reprodutiva mais tarde. Os resultados são, em geral, compatíveis com a teoria do investimento parental. Limitações do estudo e perspectivas futuras são discutidas.<br>According to the parental investment theory, it would be expected an association between maternal family environment and her reproductive behavior and, as a consequence, her patterns of parental investment on her children, with effects on their development. This study aimed to verify that association, in a sample of 37 mothers and their children (one to four years old), in a poor neighborhood of Salvador, in the state of Bahia, Brazil. We studied the family and reproductive history of the mothers and assessed the cognitive development of children, through Bayley and WIPPSI-R scales, in four assessments during three years. We found correlation between the raising environment of the mother and her subsequent reproductive patterns. These patterns were related to cognitive development of children, favoring children whose mothers started their reproductive life later. The results are, in general, compatible with the parental investment theory. Limitations of the study and future perspectives are discussed

Exploring the cxcr3 chemokine receptor with small-molecule antagonists and agonists

CXCR3 is a CXC chemokine receptor that, together with its three major ligands, CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC), is involved in inflammatory responses, mediated mainly by T cells. In several immune-related diseases, including chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), rheumatoid arthritis, multiple sclerosis, and atherosclerosis, CXCR3 and/or its ligands are found to be overexpressed, potentially indicating a role for this receptor in these diseases. Animal models have confirmed the therapeutic potential of targeting CXCR3 in the treatment of such diseases. Several peptidic, peptidomimetic, and small non-peptidomimetic CXCR3 ligands have been disclosed in the past 10 years. These ligands have served as chemical tools for the investigation of CXCR3 activation, blocking, and signaling, and some of these ligand series have been developed as potential therapeutic agents against inflammation. Computational modeling studies, facilitated by the recent developments in GPCR structural biology, together with mutagenesis and pharmacological studies, have aided in understanding how these ligands interact with CXCR3. This chapter will give an overview on how the combination of these chemical, computational, and pharmacological tools and techniques has increased our understanding of the molecular mechanisms by which small-molecule antagonists and agonists bind to CXCR3 compared to the relatively large chemokines. A detailed overview of CXCR3 ligand structure-activity relationships and structure-function relationships will be presented. This comparative analysis reveals that the full spectrum of antagonist and agonist effects on CXCR3 is now within reach by appropriate scaffolds and chemical modifications. Many of these ligands display behavior deviating from simple competition and do not interact with the chemokine binding site, providing evidence for an allosteric mode of action. Moreover, the computer-assisted molecular modeling of CXCR3 receptor-ligand interactions is discussed in view of GPCR crystal structures and mutagenesis studies of CXCR3 and other chemokine receptors. Improved insights in the interplay between CXCR3-ligand interactions and CXCR3-mediated signaling pathways potentially open up novel therapeutic opportunities in the area of inflammation