World J Stem Cells. 2014 Apr 26;6(2):111-9. doi: 10.4252/wjsc.v6.i2.111.
Progress of mesenchymal stem cell therapy for neural and retinal diseases.
1Tsz Kin Ng, Daniel Pelaez, Herman S Cheung, Geriatric Research, Education and Clinical Center, Miami Veterans Affairs Medical Center, Miami, FL 33125, United States.
Complex circuitry and limited regenerative power make central nervous system (CNS) disorders the most challenging and difficult for functional repair. With elusive disease mechanisms, traditional surgical and medical interventions merely slow down the progression of the neurodegenerative diseases. However, the number of neurons still diminishes in many patients. Recently, stem cell therapy has been proposed as a viable option. Mesenchymal stem cells (MSCs), a widely-studied human adult stem cell population, have been discovered for more than 20 years. MSCs have been found all over the body and can be conveniently obtained from different accessible tissues: bone marrow, blood, andadipose and dental tissue. MSCs have high proliferative and differentiation abilities, providing an inexhaustible source of neurons and glia for cell replacement therapy. Moreover, MSCs also show neuroprotective effects without any genetic modification or reprogramming. In addition, the extraordinary immunomodulatory properties of MSCs enable autologous and heterologous transplantation. These qualities heighten the clinical applicability of MSCs when dealing with the pathologies of CNS disorders. Here, we summarize the latest progress of MSC experimental research as well as human clinical trials for neural and retinal diseases. This review article will focus on multiple sclerosis, spinal cord injury, autism, glaucoma, retinitis pigmentosa and age-related macular degeneration.
Central nervous system; Clinical trial; Mesenchymal stem cells; Retina; Stem cell therapy
Cytotherapy. 2009;11(2):177-88. doi: 10.1080/14653240802714819.
1Department of Ophthalmology, University Eye Hospital, University of Heidelberg, Mannheim, Germany.
The non-exudative form of age-related macular degeneration (ARMD) is characterized by a progressive decay of retinal pigment epithelium cells at the posterior pole of the eye. As mesenchymal stromal cells (MSC) have been shown to differentiate into various cell types from the mesodermal and ectodermal lineages, we investigated whether we can induce a phenotype displaying retinal pigment epithelium (RPE) characteristics.
The differentiation of human lipo-aspirate-derived MSC toward the RPE lineage was triggered by exposure to conditioned medium from either human or porcine RPE cells. In a second approach we tested whether adding vasoactive intestinal peptide (VIP) is capable of further modifying differentiation processes. Resulting cell populations were assessed for expression of RPE-specific markers by immunofluorescence, quantitative real time (RT)-polymerase chain reaction (PCR) and Western blotting. The potential for pigment synthesis was assessed by the response to melanocyte-stimulating hormone (MSH).
Following culture of undifferentiated MSC with RPE-conditioned medium and/or VIP, expression of typical RPE markers bestrophin, cytokeratins 8 and 18 and RPE 65 was induced. MSH induced the formation of pigmented granula in differentiated MSC.
MSC are shown to express RPE markers upon induction with either RPE-conditioned medium and/or VIP. The gain of basic functional features of RPE cells was indicated by melanin synthesis. This alludes to a differentiation potential of MSC into the neuroectodermal lineage, yielding cells with phenotypic characteristics of RPE cells.
Prog Retin Eye Res. 2014 Sep;42:130-44. doi: 10.1016/j.preteyeres.2014.06.002. Epub 2014 Jun 13.
Stem cells as source for retinal pigment epithelium transplantation.
1Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
2Ophthalmology, S.Bi.Bi.T. Department, University of Parma, Parma, Italy.
3Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
Inherited maculopathies, age related macular degeneration and some forms of retinitis pigmentosa are associated with impaired function or loss of the retinal pigment epithelium (RPE). Among potential treatments, transplantation approaches are particularly promising. The arrangement of RPE cells in a well-defined tissue layer makes the RPE amenable to cell or tissue sheet transplantation. Different cell sources have been suggested for RPE transplantation but the development of a clinical protocol faces several obstacles. The source should provide a sufficient number of cells to at least recover the macula area. Secondly, cells should be plastic enough to be able to integrate in the host tissue. Tissue sheets should be considered as well, but the substrate on which RPE cells are cultured needs to be carefully evaluated. Immunogenicity can also be an obstacle for effective transplantation as well as tumorigenicity of not fully differentiated cells. Finally, ethical concerns may represent drawbacks when embryo-derived cells are proposed for RPE transplantation. Here we discuss different cell sources that became available in recent years and their different properties. We also present data on a new source of human RPE. We provide a protocol for RPE differentiation of retinal stem cells derived from adult ciliary bodies of post-mortem donors. We show molecular characterization of the in vitro differentiated RPE tissue and demonstrate its functionality based on a phagocytosis assay. This new source may provide tissue for allogenic transplantation based on best matches through histocompatibility testing.
KEYWORDS: Bestrophin 1; Beta5-integrin; CRALBP; LRAT; MITF; OA1; RPE65; Retinal neurospheres; Retinal stem cells
Medicine (Baltimore). 2014 Dec 2. doi: 10.1097/MD.0000000000000355
Preliminary Study on Electrophysiological Changes After Cellular Autograft in Age-Related Macular Degeneration
Limoli PG1, Vingolo EM2,3, Morales MU4, Nebbioso M5, Limoli C1.
1Low Vision Research of Milan, Milan, Italy
2Department of Ophthalmology, A. Fiorini Hospital, Terracina, Italy
3Polo Pontino, Padova, Italy
4CenterVue, Padova, Italy
5Department of Sense Organs, Faculty of Medicine and Odontology, Sapienza University of Rome, Rome, Italy
Evolving atrophic macular degeneration represents at least 80% of all macular degenerations and is currently without a standardized care. Autologous fat transplantation efficacy was demonstrated by several studies, as these cells are able to produce growth factors. The aim of the work was to demonstrate possible therapeutic effect of the joined suprachoroidal graft of adipocytes, adipose-derived stem cells (ADSCs) in stromal vascular fractions (SVFs) of adipose tissue, and platelet-rich plasma (PRP).
Twelve eyes in 12 dry age-related macular degeneration (AMD) patients, aged 71.25 (SD ± 6.8) between 62 and 80 years, were analyzed. A complete ocular evaluation was performed using best corrected visual acuity (BCVA), retinographic analysis, spectral-domain optical coherence tomography, microperimetry, computerized visual field, and standard electroretinogram (ERG). Each eye received a cell in graft between choroid and sclera of mature fat cells and ADSCs in SVF enriched with PRP by means of the variant second Limoli (Limoli retinal restoration technique [LRRT]). In order to test if the differences pre- and post-treatment were significant, the Wilcoxon signed-rank test has been performed.
Adverse effects were not reported in the patients. After surgery with LRRT, the most significant increase in the ERG values was recorded by scotopic rod-ERG (answer coming from the rods), from 41.26 to 60.83 μV with an average increase of 47.44% highly significant (P < 0.05). Moderately significant was the one recorded by scotopic maximal ERG (answer coming from the rods and cones), from 112.22 to 129.68 μV with an average increase of 15.56% (P < 0.1).
Cell-mediated therapy based on growth factors used appears interesting because it can improve the retinal functionality responses in the short term. The ERG could, therefore, be used to monitor the effect of cell-mediated regenerative therapies.