Clinical Application of Mesenchymal Stem Cells in the …

Division of Hematology, Department of Medicine, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA

Copyright 2011 Yi Lin and William J. Hogan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Mesenchymal stem cells (MSCs) represent a heterogeneous population of stromal cells with pluripotent mesenchymal differentiation potential. They have been found to have immunosuppressive properties and the ability to modulate angiogenesis and endogenous tissue repair by in vitro and animal studies. Clinical trials have examined the utility of these cells in autoimmune and inflammatory conditions. In particular, in allogeneic hematopoietic stem cell transplant (HSCT), multiple studies have been conducted to explore the use of MSC to treat acute and chronic graft-versus-host disease (GVHD) and for cotransplantation with HSCT to promote HSC engraftment and prevent GVHD. We review here the results of these studies and discuss some challenges of this treatment modality in this disease setting.

Mesenchymal stem cell and multipotent mesenchymal stromal cells are both designated MSC nomenclature by the latest consensus statement from the International Society for Cellular Therapy (ISCT) [1]. This is a group of heterogeneous plastic-adherent cells that can be isolated from bone marrow (BM), adipose tissue, placenta, cord blood, and other tissues. The name MSC simply implies the mesenchymal origin of these cells and is not necessarily the limit of their differentiation potential. Given the heterogeneity of the stromal cell compartment and the limited number of these cells that have true stem-cell-like properties, consistent characterizations of MSC were proposed to maximize intersample equivalency in data comparison [2]. Three criteria are now commonly used among researchers: (1)adherence to plastic in in vitro culture, (2)surface antigen expression positivity (95%) for CD 105, CD73, CD90 and negativity (2%) for lineage markers including CD45, CD34, CD14 or 11b, CD79 alpha or CD19, and HLA-DR,(3)capacity for differentiation in vitro into osteoblasts, adipocytes, and chrondroblasts.

In vitro MSC have been shown to exert immunosuppressive effects via direct suppression of T and B lymphocytes, NK cell, and dendritic cell functions [312]. They can also secrete cytokines important for angiogenesis, tissue repair, and immune modulation such as VEGF, IL-6, IL11, M-CSF, and stem cell factor [1315]. In animal models, some reports suggest prolonged survival of skin and solid organ grafts with MSC infusion [4, 1618] while protection from graft-versus-host disease (GVHD) by MSC in the mouse model is less clear [1921]. This is partially attributed to the complex biology of these cells compounded by variations in activation of their potential functions by different culture techniques across different labs. Interspecies differences in MSC functions and discrepancies between in vitro and in vivo studies have also been described [22].

In recent decade, there has been intense interest in clinical applications of MSC for modulation of immunity and endogenous repair. At the time of writing, there are currently 179 clinical trials using MSC registered at clinicaltrials.gov. Crohns disease, cardiac ischemia, limb ischemia, amyotrophic lateral sclerosis, diabetes, multiple sclerosis, and liver cirrhosis are just a few of the conditions listed. Graft-versus-host disease (GVHD) was one of the first conditions to be studied.

Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant or donor lymphocyte infusion. This can occur in up to 3050% of patients despite HLA-matched sibling transplant and even more frequently in HLA-mismatched unrelated donor transplants (6080%) [23]. Corticosteroids remain the first-line treatment; however, despite the addition of other steroid sparing agents such as calcineurin inhibitors, prognosis for steroid-refractory aGVHD patients remains poor with 5-year survival of less than 30%. Furthermore, many patients may either progress from aGVHD or develop de novo chronic GVHD (cGVHD) with similar high risk of morbidity and mortality [23]. MSC has been examined for use both in the prevention and treatment of acute and chronic GVHD. We review here the clinical trials of MSC in the prevention and treatment of GVHD and discuss some of the challenges that remain to be addressed.

The first case of MSC infusion for treatment of GVHD was described by Le Blanc et al. in 2004 [24]. A nine-year-old boy with acute lymphoblastic leukemia received a matched unrelated donor peripheral blood stem cell transplant after his third remission. He developed rash on day 11, diarrhea on day 22, and liver enzyme elevation on day 25 after transplant. He did not respond to corticosteroids, extracorporeal photochemotherapy, infliximab, daclizumab, mycophenolate mofetil, and methotrexate. By day 70, aGVHD had progressed to grade IV severity, and on day 73, he received an IV infusion of 2 106cells/kg of MSC from his mother. No adverse events were noted with the infusion, and it was reported that symptoms began to improve within 5 days and resolved within two weeks. The patient developed recurrent GVHD at day 150, shortly after his immunosuppression was discontinued to treat minimal recurrent disease. He received another infusion of MSC from his mother at half of the first dose. He was reported to have a complete response of his GVHD and remission of ALL. He subsequently died 19 months after transplant from recurrence of gut GVHD and respiratory failure from pneumonia [25].

This patient was also included in a pilot study reported by Ringden et al. [25] of eight patients with steroid-resistant grade III to IV aGVHD and one patient with chronic GVHD who were treated with MSC between October 2001 and March 2005. Two patients were children, and seven were adults. MSC was cultured from bone marrow aspirates of healthy donors and used fresh from culture at or under four passages. Flow cytometry analysis for phenotype was performed prior to release. Six patients received one infusion, and three patients received two infusions. The median MSC dose was 1 106cells/kg (range 0.79). Of the twelve infusions, two were from HLA-identical donors, six from haploidentical donors, and four from mismatched unrelated donors. Two patients who received two MSC infusions had different donors for each infusion. The median time between transplant and MSC infusion was 108 days (range 32283 days) and between onset of GVHD symptoms and infusion was 37 days (range 790 days). There were no adverse events reported from the MSC infusions, and six of the eight aGVHD patients had complete response. The patient with chronic GVHD was reported to have a transient liver response without any skin response. Median response time was not reported. In addition to the pediatric patient previously described in Le Blanc et al. 04, one of the remaining two patients who received two infusions did not have significant response to the first infusion of 0.7 106cells/kg but was reported to have had a complete response with second infusion of 2 106cells/kg. The third patient who received two infusions also had an escalation of dosage from 0.7 to 1.3 106cells/kg. He did not respond to either infusion and died eight days later from multiorgan failure. No patient developed chronic GVHD.

In autopsy of two nonresponders, HLA-specific DNA from MSC donor was found in the GI lymph nodes of
the nonresponder who died eight days after infusion, but not identified in another nonresponder who died three weeks after MSC infusion. In another patient who had a complete response to MSC infusion who died 19 months later from recurrence of GVHD, MSC donor DNA was not found at autopsy [25].

See the rest here:
Clinical Application of Mesenchymal Stem Cells in the ...