Abstract
BackgroundMarrow stromal cells (MSC), the non-hematopoietic precursor cells in bone marrow, are being investigated for therapeutic potential in CNS disorders. Although in vitro studies have suggested that MSC may be immunologically inert, their immunogenicity following transplantation into allogeneic recipients is unclear. The primary objective of this study was to investigate the cellular immune response to MSC injected into the striatum of allogeneic recipients (6-hydroxydopamine [6-OHDA]-hemilesioned rats, an animal model of Parkinson's disease [PD]), and the secondary objective was to determine the ability of these cells to prevent nigrostriatal dopamine depletion and associated motor deficits in these animals.Methods5-Bromo-2-deoxyuridine (BrdU) – labeled MSC from two allogeneic sources (Wistar and ACI rats) were implanted into the striatum of adult Wistar rats at the same time as 6-OHDA was administered into the substantia nigra. Behavioral tests were administered one to two weeks before and 16–20 days after 6-OHDA lesioning and MSC transplantation. Immunocytochemical staining for T helper and T cytotoxic lymphocytes, microglia/macrophages, and major histocompatibility class I and II antigens was performed on post-transplantation days 22–24. MSC were detected with an anti-BrdU antibody.ResultsTissue injury due to the transplantation procedure produced a localized cellular immune response. Unexpectedly, both sources of allogeneic MSC generated robust cellular immune responses in the host striatum; the extent of this response was similar in the two allograft systems. Despite these immune responses, BrdU+ cells (presumptive MSC) remained in the striatum of all animals that received MSC. The numbers of remaining MSC tended to be increased (p = 0.055) in rats receiving Wistar MSC versus those receiving ACI MSC. MSC administration did not prevent behavioral deficits or dopamine depletion in the 6-OHDA-lesioned animals.ConclusionMSC, when implanted into the striatum of allogeneic animals, provoke a marked immune response which is not sufficient to clear these cells by 22–24 days post-transplantation. In the experimental paradigm in this study, MSC did not prevent nigrostriatal dopamine depletion and its associated behavioral deficits. Additional studies are indicated to clarify the effects of this immune response on MSC survival and function before initiating trials with these cells in patients with PD or other neurodegenerative disorders.
Highlights
Marrow stromal cells (MSC), the non-hematopoietic precursor cells in bone marrow, are being investigated for therapeutic potential in central nervous system (CNS) disorders
Our intention was to generate partial, rather than complete, lesions, similar to the extent of nigrostriatal dopamine depletion in Parkinson's disease (PD) patients; our preliminary studies found that this concentration of 6-OHDA produced a 70–95% loss of striatal dopamine in most animals
Evaluation for statistical differences between treatment groups using the Kruskal-Wallis test was not useful because of the large variation in behavioral deficits and small sample sizes. (The sample sizes were chosen on the basis of a power analysis from data from a pilot investigation performed in our laboratory; the lesion size varied more in the present study than it did in the pilot study.) Data are presented in Fig. 1 as scatter plots of the individual behavioral scores as a function of the degree of lesioning
Summary
Marrow stromal cells (MSC), the non-hematopoietic precursor cells in bone marrow, are being investigated for therapeutic potential in CNS disorders. Intrastriatal implantation of fetal mesencephalic tissue has resulted in long-term reductions of motor deficits [1,2] and normalization of striatal dopamine levels [3] in some patients, but this approach is limited by ethical and practical concerns, as well as the development of dyskinesias. More recent studies have suggested that stem cells may be useful in treating PD [5,6,7] These cells offer significant advantages over fetal tissue for treatment of PD, including their ability to be expanded in culture and receive transfected genes and their potential for migration and differentiation in host tissue [8]. Ethical and logistical issues similar to those for fetal mesencephalon transplantation apply to human embryonic stem cell therapy
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