There is increasing evidence that transplanted adult stem

cells remain undifferentiated and often are cleared after a short time.

However, these short-lived stem cells still promote recovery in a variety of

injury settings, suggesting that their beneficial effects are mediated

primarily through an impact on host cells and tissues. This has been attributed

to mechanisms involving release of factors that are immunomodulatory and/or

tolerogenic. Multipotent adult progenitor cells

(MAPC^®), a novel, proprietary adult bone marrow-derived stem cell

product, are efficacious in several pre-clinical animal models of injury and

disease including ischemic stroke, traumatic brain injury (TBI), spinal cord

injury (SCI), acute myocardial infarct, solid organ transplant, and graft

versus host disease. In each setting, MAPC exert effects through a variety of

anti-inflammatory and pro-angiogenic, healing pathways. T regulatory cells, a subpopulation of T

cells, are integral to establishing tolerance within the body, controlling aberrant

autoimmune reactions, and dampening the inflammatory response. One possible

mechanism by which MAPC^® may exert such wide-acting immunomodulatory

influences would be by increasing the pool of T regulatory cells. In fact, we

observe an upregulation of T regulatory cells upon treatment with MAPC^®

in rat models of TBI and SCI and in the context of liver allograft

transplantation, we have human clinical data showing a transient increase in

peripheral T regulatory cells. In order to further test the role of MAPC in T

reg induction and to begin to elucidate the mechanism of induction, we

established an in vitro assay. We co-cultured

MAPC with human PBMCs for 7 days and analyzed the cell population for the

presence of FoxP3⁺ T regulatory cells. There is a reproducible, donor-independent

2-fold induction of FoxP3⁺ T regulatory cells. Induction is concomitant

with increased levels of TGF-β in the culture supernatant and is dependent upon

the dose of MAPC. Active research is

ongoing to understand the mechanism driving T regulatory cell induction and to

determine the quality of suppressor cells being generated.

CITATION INFORMATION: Stubblefield S, Williams N, Ting A. In Vitro Induction of T Regulatory Cells by Multipotent Adult Progenitor Cells. Am J Transplant. 2016;16 (suppl 3).

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