Mesenchymal stromal cells lose their immunosuppressive potential after allotransplantation

Prigozhina, Tatyana B.; Khitrin, Sofia; Elkin, Gregory; Eizik, Osnat; Morecki, Shoshana; Slavin, Shimon

doi:10.1016/j.exphem.2008.04.022

Cited by 102 publications

(71 citation statements)

References 44 publications

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“…In line with this, the results of our study also challenge the emerging concept that in humans iNOS has a pivotal role in MSC-mediated immunosuppression in vivo, 18 as in the human setting the role of IDO and others mechanisms appears more prominent. 2,[20][21][22][23] In addition, the outlined functional differences between murine and human MSCs might provide a clue to the partially discrepant results on the therapeutic efficacy of MSC obtained in preclinical murine models [24][25][26] and clinical studies. 27 From a clinical perspective, the identification of a cell autonomous antimicrobial effector function in human MSCs is intriguing.…”

Section: Discussionmentioning

confidence: 99%

Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase

et al. 2011

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Human multipotent mesenchymal stromal cells (MSCs) exhibit multilineage differentiation potential, support hematopoiesis, and inhibit proliferation and effector function of various immune cells. On the basis of these properties, MSC are currently under clinical investigation in a range of therapeutic applications including tissue repair and immune-mediated disorders such as graft-versus-host-disease refractory to pharmacological immunosuppression. Although initial clinical results appear promising, there are significant concerns that application of MSC might inadvertently suppress antimicrobial immunity with an increased risk of infection. We demonstrate here that on stimulation with inflammatory cytokines human MSC exhibit broad-spectrum antimicrobial effector function directed against a range of clinically relevant bacteria, protozoal parasites and viruses. Moreover, we identify the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) as the underlying molecular mechanism. We furthermore delineate significant differences between human and murine MSC in that murine MSC fail to express IDO and inhibit bacterial growth. Conversely, only murine but not human MSC express inducible nitric oxide synthase on cytokine stimulation thus challenging the validity of murine in vivo models for the preclinical evaluation of human MSC. Collectively, our data identify human MSC as a cellular immunosuppressant that concurrently exhibits potent antimicrobial effector function thus encouraging their further evaluation in clinical trials.

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Section: Discussionmentioning

confidence: 99%

Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase

et al. 2011

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“…MSCs have been shown to be immune-privileged, in that they avoid allogenic rejection in humans by failing to induce a proliferative T cell response. Coupled with their immunomodulatory advantage, although potentially less effective in vivo than in vitro [49], this immune-privileged status raises the possibility of an 'off-the-shelf' cellular product appropriate to any recipient. MSCs can also be obtained from autologous sources, including renal patients [50], making them ideal vehicles for the delivery of others genes known to be beneficial in kidney repair.…”

Section: Mesenchymal Stromal Cells (Mscs)mentioning

confidence: 99%

Stem cell options for kidney disease

Hopkins

Rae

et al. 2008

The Journal of Pathology

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Chronic kidney disease (CKD) is increasing at the rate of 6-8% per annum in the US alone. At present, dialysis and transplantation remain the only treatment options. However, there is hope that stem cells and regenerative medicine may provide additional regenerative options for kidney disease. Such new treatments might involve induction of repair using endogenous or exogenous stem cells or the reprogramming of the organ to reinitiate development. This review addresses the current state of understanding with respect to the ability of non-renal stem cell sources to influence renal repair, the existence of endogenous renal stem cells and the biology of normal renal repair in response to damage. Understanding repair options via an understanding of renal developmentThe prevalence and incidence of chronic kidney disease (CKD) is increasing at 6-8% per annum in the USA alone, largely as a result of increased prevalence of diabetes and obesity [1]. To understand what might be possible with respect to cellular therapies or regenerative medicine for the kidney, one first needs to consider what is understood about normal renal development and response to injury. The kidney has been classically regarded as an organ with minimal cellular turnover and no capacity for regeneration. The subsequent identification of stem cells in a number of such organs, including the brain, has challenged this view. However, the dogma remains that the kidney reaches a maximal complement of nephrons and then loses these over time [2]. This dogma is drawn from our understanding of the development of this organ. The progenitor population during developmentThe kidney is mesodermal in origin and develops from two populations derived from intermediate mesoderm, the ureteric bud (UB) and the metanephric mesenchyme (MM). While an even broader potential had been proposed [3], genetic and lineage analyses have confirmed that the MM gives rise to all portions of the nephron other than the collecting ducts and also gives rise to elements of the renal interstitium [4][5][6]. The UB gives rise to the ureter and collecting ducts only. The MM is apparently not homogeneous but forms condensed mesenchyme around the tips of the branching UB. This cap mesenchyme (CM) contains self-renewing progenitors capable of generating all cells of the nephron other than the collecting ducts via an initial mesenchyme-epithelial transition (MET) event throughout the prenatal developmental period [6]. The continued expression of the transcription factor Six2 in CM is required for maintenance of this stem cell population during kidney development [5]. As the UB branches and extends through the MM, individual MET events occur at the underside of each tip to form a new nephron [2]. This nephron endowment therefore proceeds from the centre of the kidney out to the periphery, with the CM stem cell field remaining on the outer edge of the expanding organ. Endowment of new nephrons is restricted to prenatal development in humans, while in rodents it persists only until the imm...

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“…Nevertheless, it has also been reported that the immune‐suppressive ability of MSCs observed in in vitro settings is not effective enough for transplanted allogeneic MSCs to establish immune privilege in various disease conditions in vivo 4, 5, 9, 10. Westrich et al observed that ≈1% of total injected allogeneic MSCs survived at day 2 after intramyocardial injection (a similar ratio to syngeneic MSCs, calculated from their data) in a rat subacute MI model, whereas most allogeneic, but not syngeneic, MSCs subsequently disappeared by day 7 4.…”

Section: Introductionmentioning

confidence: 99%

Allogeneic Mesenchymal Stromal Cells Transplanted Onto the Heart Surface Achieve Therapeutic Myocardial Repair Despite Immunologic Responses in Rats

Tano

Kaneko

Ichihara

et al. 2016

JAHA

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BackgroundTransplantation of allogeneic mesenchymal stromal cells (MSCs) is a promising treatment for heart failure. We have shown that epicardial placement of cell sheets markedly increases donor cell survival and augments therapeutic effects compared with the current methods. Although immune rejection of intramyocardially injected allogeneic MSCs have been suggested, allogeneic MSCs transplanted on the heart surface (virtual space) may undergo different courses. This study aimed to elucidate immunologic response against epicardially placed allogeneic MSCs, rejection or acceptance of these cells, and their therapeutic effects for heart failure.Methods and ResultsAt 4 weeks after coronary artery ligation, Lewis rats underwent epicardial placement of MSC sheets from syngeneic Lewis or allogeneic Fischer 344 rats or sham treatment. At days 3 and 10 after treatment, similar ratios (≈50% and 30%, respectively) of grafted MSCs survived on the heart surface in both MSC sheet groups. By day 28, survival of syngeneic MSCs was substantially reduced (8.9%); survival of allogeneic MSCs was more extensively reduced (0.2%), suggesting allorejection. Correspondingly, allogeneic MSCs were found to have evoked an immunologic response, albeit low level, as characterized by accumulation of CD4+ T cells and upregulation of interleukin 6. Despite this alloimmune response, the allogeneic MSC sheet achieved myocardial upregulation of reparative factors, enhanced repair of the failing myocardium, and improved cardiac function to the equivalent degree observed for the syngeneic MSC sheet.ConclusionsAllogeneic MSCs placed on the heart surface evoked an immunologic response; however, this allowed sufficient early phase donor cell survival to induce equivalent therapeutic benefits to syngeneic MSCs. Further development of this approach toward clinical application is warranted.

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Mesenchymal stromal cells lose their immunosuppressive potential after allotransplantation

Cited by 102 publications

References 44 publications

Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase

Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase

Stem cell options for kidney disease

Allogeneic Mesenchymal Stromal Cells Transplanted Onto the Heart Surface Achieve Therapeutic Myocardial Repair Despite Immunologic Responses in Rats

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