The Immunomodulatory and Neuroprotective Effects of Mesenchymal Stem Cells (MSCs) in Experimental Autoimmune Encephalomyelitis (EAE): A Model of Multiple Sclerosis

Abstract: Mesenchymal stem cells (MSCs) are multipotent cells that differentiate into the mesenchymal lineages of adipocytes, osteocytes and chondrocytes. MSCs can also transdifferentiate and thereby cross lineage barriers, differentiating for example into neurons under certain experimental conditions. MSCs have anti-proliferative, anti-inflammatory and anti-apoptotic effects on neurons. Therefore, MSCs were tested in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), for their effectiveness in modulating the pathogenic process in EAE to develop effective therapies for MS. The data in the literature have shown that MSCs can inhibit the functions of autoreactive T cells in EAE and that this immunomodulation can be neuroprotective. In addition, MSCs can rescue neural cells via a mechanism that is mediated by soluble factors, which provide a suitable environment for neuron regeneration, remyelination and cerebral blood flow improvement. In this review, we discuss the effectiveness of MSCs in modulating the immunopathogenic process and in providing neuroprotection in EAE

The Immunomodulatory Features of Mesenchymal Stromal Cells Derived from Wharton\u2019s Jelly, Amniotic Membrane and Chorionic Villi: In Vitro and In Vivo Data.

This chapter focuses on the immunomodulatory properties of placental mesenchymal stromal cells (MSCs) derived from the amniotic membrane, umbilical cord, and chorionic villi. Within the amniotic membrane (AM), we discuss the immunomodulatory properties of the two main cell populations that can be isolated from AM: human amniotic mesenchymal stromal cells (hAMSCs) and human amniotic epithelial cells (hAECs). Within the umbilical cord, several compartments have been described, including the amniotic compartment, the Wharton\u2019s jelly (WJ) compartment, and the vascular and perivascular compartment, but herein attention is focused on the properties of human WJ MSCs (hWJMSCs). Since different isolation protocols have been used, umbilical cord matrix stem cells, umbilical cord stromal cells, and human umbilical cord MSCs (herein hUCMSCs) were also included. This chapter also discusses the properties of human chorionic villi/placenta MSCs (hCVMSCs/hPLMSCs). The nomenclature of placental MSCs used in this chapter was chosen on the basis of consensus from the First International Workshop on Placenta-Derived Stem Cells for hAECs and hAMSCs (Parolini et al. 2008). Since different nomenclature is reported for the other placental MSCs, the following nomenclature is used: hWJMSCs/hUCMSCs for MSCs from WJ (and from umbilical cord where described isolation protocols include WJ) and hCVMSCs/hPLMSCs for MSCs from chorionic villi and the placenta/trophoblast compartment

Histology of CMSCs and DMSCs transplants.

<p>Cross sections are representative of CMSCs transplants (A-B) and DMSCs transplants (E-F) after 8 weeks stained with Haematoxylin and Eosin (H&E). In the transplant, the HA/TCP carrier surfaces (dashed lines) are lined with new bone formation (b), areas of immature bone (ob) together with the surrounding fibrous and hematopoietic tissue (a) and blood vessel (bv). Representative BrdU staining for localization of implanted CMSCs (C-D) and DMSCs (G-H). BrdU-stained implanted cells were found lining the mineralized matrix (black arrows) and surrounding fibrous tissue. Brown nuclear staining is indicative of DAB reactivity. There was no immunoreactivity present in sections stained with isotype-matched antibodies. HA/TCP: hydroxyapatite/tricalcium phosphate particles. Magnification is 100X and scalebar is 500 μm.</p

Antibodies used for characterizing CMSCs and DMSCs by flow cytometry.

<p>^a anti-human antibodies raised in mice.</p><p>Antibodies used for characterizing CMSCs and DMSCs by flow cytometry.</p

CMSC phenotypic characterization.

<p>A. (i) Bright field microscopy image of CMSCs at P0. Magnification is 100X and scalebar is 100 μm. (ii) CMSCs from placentae of male newborns were analyzed using interphase FISH on MSC nuclei. CMSCs showed one chromosome X (Spectrum Green) and one chromosome Y (Spectrum Orange) signals. Cell nuclei were stained blue with DAPI. Magnification is 630X. B. Primary CMSCs cell surface markers expression. Histograms of representative primary CMSC at P3 depicting the expression of CD90, CD146, CD166, CD44, CD73, CD105, CD45, HLA-DR, and CD19. The red histogram shows the MSC marker antibody staining while the white histogram shows the corresponding isotype control antibody staining. PE: phycoerythrin dye, APC: allophycocyanin dye, APC-Cy7: allophycocyanin-Cy7 dye. C. Representative photomicrographs showing CMSCs differentiation into mesenchymal lineages. (i) Osteogenic differentiation, Alizarin Red staining in cells after 5weeks growth in osteogenic induction medium. Arrows show calcium depositions. (ii) Adipogenic differentiation, Oil Red O staining in cells after 14 days growth in adipogenic induction medium. Arrows show fat droplets. (iii) Chondrogenic differentiation, Safranin O staining for proteoglycans depositions in cells after 21 days growth in chondrogenic induction medium. Inset shows control uninduced CMSCs. Scalebar is 100 μm.</p