Structure and function of the blood–brain barrier

https://www.pure.ed.ac.uk/ws/files/14186931/A_Perivascular_Origin_for_Mesenchymal_Stem_Cells_in_Multiple_Human_Organs.pdf

A perivascular origin for mesenchymal stem cells in multiple human organs

Mesenchymal stem cells (MSCs) are a heterogeneous subset of stromal stem cells that can be isolated from many adult tissues. They can differentiate into cells of the mesodermal lineage, such as adipocytes, osteocytes and chondrocytes, as well as cells of other embryonic lineages. MSCs can interact with cells of both the innate and adaptive immune systems, leading to the modulation of several effector functions. After in vivo administration, MSCs induce peripheral tolerance and migrate to injured tissues, where they can inhibit the release of pro-inflammatory cytokines and promote the survival of damaged cells. This Review discusses the targets and mechanisms of MSC-mediated immunomodulation and the possible translation of MSCs to new therapeutic approaches.

Mesenchymal stem cells in health and disease

Mesenchymal stem cells (MSCs) are multipotent cells which can give rise to mesenchymal and non-mesenchymal tissues in vitro and in vivo. Whereas in vitro properties such as (trans)differentiation capabilities are well known, there is little information regarding natural distribution and biology in the living organism. To investigate the subject further, we generated long-term cultures of cells with mesenchymal stem cell characteristics from different organs and tissues from adult mice. These populations have morphology, immunophenotype and growth properties similar to bone marrow-derived MSCs. The differentiation potential was related to the tissue of origin. The results indicate that (1) cells with mesenchymal stem characteristics can be derived and propagated in vitro from different organs and tissues (brain, spleen, liver, kidney, lung, bone marrow, muscle, thymus, pancreas); (2) MSC long-term cultures can be generated from large blood vessels such as the aorta artery and the vena cava, as well as from small vessels such as those from kidney glomeruli; (3) MSCs are not detected in peripheral blood. Taken together, these results suggest that the distribution of MSCs throughout the post-natal organism is related to their existence in a perivascular niche. These findings have implications for understanding MSC biology, and for clinical and pharmacological purposes.

/pdf/mesenchymal-stem-cells-reside-in-virtually-all-post-natal-4s1txmgth3.pdf

Mesenchymal stem cells reside in virtually all post-natal organs and tissues

Bone marrow stem cells give rise to a variety of hematopoietic lineages and repopulate the blood throughout adult life. We show that, in a strain of mice incapable of developing cells of the myeloid and lymphoid lineages, transplanted adult bone marrow cells migrated into the brain and differentiated into cells that expressed neuron-specific antigens. These findings raise the possibility that bone marrow-derived cells may provide an alternative source of neurons in patients with neurodegenerative diseases or central nervous system injury.

https://science.sciencemag.org/content/sci/290/5497/1779.full.pdf

Turning Blood into Brain: Cells Bearing Neuronal Antigens Generated in Vivo from Bone Marrow

In spite of the advances in the knowledge of adult stem cells (ASCs) during the past few years, their natural activities in vivo are still poorly understood. Mesenchymal stem cells (MSCs), one of the most promising types of ASCs for cell-based therapies, are defined mainly by functional assays using cultured cells. Defining MSCs in vitro adds complexity to their study because the artificial conditions may introduce experimental artifacts. Inserting these results in the context of the organism is difficult because the exact location and functions of MSCs in vivo remain elusive; the identification of the MSC niche is necessary to validate results obtained in vitro and to further the knowledge of the physiological functions of this ASC. Here we show an analysis of the evidence suggesting a perivascular location for MSCs, correlating these cells with pericytes, and present a model in which the perivascular zone is the MSC niche in vivo, where local cues coordinate the transition to progenitor and mature cell phenotypes. This model proposes that MSCs stabilize blood vessels and contribute to tissue and immune system homeostasis under physiological conditions and assume a more active role in the repair of focal tissue injury. The establishment of the perivascular compartment as the MSC niche provides a basis for the rational design of additional in vivo therapeutic approaches. This view connects the MSC to the immune and vascular systems, emphasizing its role as a physiological integrator and its importance in tissue repair/regeneration.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1634/stemcells.2007-1122

In search of the in vivo identity of mesenchymal stem cells

In spite of the attention given to the study of mesenchymal stem cells (MSCs) derived from the bone marrow (BM) of humans and other species, there is a lack of information about murine MSCs. We describe the establishment of conditions for the in vitro expansion of plastic-adherent cells from murine BM for over 50 passages, and provide their characterization regarding morphology, surface marker profile and growth kinetics. These cells were shown to differentiate along osteogenic and adipogenic pathways, and to support the growth and differentiation of haematopoietic stem cells, and were thus operationally defined as murine mesenchymal stem cells (mMSCs). mMSCs were positive for the surface markers CD44, CD49e, CD29 and Sca-1, and exhibited a homogeneous, distinctive morphology. Their frequency in the BM of adult BALB/c and C57Bl/6 mice, normal or knockout for the alpha-L-iduronidase (IDUA) gene, was preliminarily estimated to be 1 per 11,300-27,000 nucleated cells. The emergence of a defined methodology for the culture of mMSCs, as well as a comprehensive understanding of their biology, will make the development of cellular and genetic therapy protocols in murine models possible, and provide new perspectives in the field of adult stem cells research.

https://onlinelibrary.wiley.com/doi/pdf/10.1046/j.1365-2141.2003.04669.x

Murine marrow-derived mesenchymal stem cell: isolation, in vitro expansion, and characterization.

Mesenchymal stem cells (MSCs) are adult stem cells able to give rise to mature mesenchymal cell types. Plastic-adherent cells are operationally defined as MSCs based on their ability to proliferate and differentiate into cells such as osteoblasts, adipocytes and chondrocytes. In the past ten years, cultured MSCs have been shown to exhibit great plasticity in culture, as they can differentiate into cells with ectodermal and endodermal characteristics, suggesting their use as a source of cells to treat different diseases. More recently, cultured MSCs were found to secrete various bioactive molecules that display anti-apoptotic, immunomodulatory, angiogenic, anti-scarring, and chemoattractant properties, providing a basis for their use as tools to create local regenerative environments in vivo. Whereas the properties of cultured MSCs have been studied for a long time, their exact location in vivo is slowly becoming apparent as evidence indicates that pericytes behave as stem cells throughout the organism. In this review, we discuss some aspects of MSC basic biology, the methodology involved in MSC culture, and some clinical and pre-clinical applications of cultured MSCs.

Methodology, biology and clinical applications of mesenchymal stem cells.

The adeno-associated virus (AAV) has rapidly gained popularity in gene therapy since the establishment of the first AAV2 infectious clone, in 1982, due to some of their distinguishing characteristics such as lack of pathogenicity, wide range of infectivity, and ability to establish long-term transgene expression. Notably over the past decade, this virus has attracted considerable interest as a gene therapy vector, and about 85% of the currently available 2,041 PubMed references on adeno-associated viruses have been published during this time. The exponential progress of AAV-based vectors has been made possible by the advances in the knowledge of the virology and biology of this virus, which allows great improvement in AAV vectors construction and a better comprehension of their operation. Moreover, with the recent discovery of novel AAV serotypes, there is virtually one preferred serotype for nearly every organ or tissue to target. Thus, AAV-based vectors have been successfully overcoming the main gene therapy challenges such as transgene maintenance, safety and host immune response, and meeting the desirable vector system features of high level of safety combined with clinical efficacy and versatility in terms of potential applications. Consequently, AAV is increasingly becoming the vector of choice for a wide range of gene therapy approaches. This report will highlight the state of the art of AAV-based vectors studies and the advances on the use of AAV vectors for several gene therapy approaches.

/pdf/the-state-of-the-art-of-adeno-associated-virus-based-vectors-pz17mc68s1.pdf

Nance Beyer Nardi

Papers

Mesenchymal stem cells reside in virtually all post-natal organs and tissues

In search of the in vivo identity of mesenchymal stem cells

Murine marrow-derived mesenchymal stem cell: isolation, in vitro expansion, and characterization.

Methodology, biology and clinical applications of mesenchymal stem cells.

The state of the art of adeno-associated virus-based vectors in gene therapy