Host factors that impact the biodistribution and persistence of multipotent adult progenitor cells

Abstract

Multipotent adult progenitor cells (MAPCs) are marrow-derived pluripotent stem cells with a broad differentiation potential. We sought to identify factors that affect adoptively transferred MAPCs. In vitro, MAPCs expressed low levels of major histocompatibility complex (MHC) antigens, failed to stimulate CD4 ؉ and CD8 ؉ T-cell alloresponses, and were targets of NK cytolysis. To study in vivo biodistribution, we labeled MAPCs with luciferase for sequential quantification of bioluminescence and DsRed2 for immunohistochemical analysis. C57BL /6 MAPCs were infused intravenously into C57BL /6, Rag-2 ؊/؊ (T-and B-cell-deficient), and Rag-2 ؊/؊ /IL-2R␥ c ؊/؊ (T-, B-, and NK-cell-deficient) mice. In C57BL /6 mice, MAPCs were transiently detected only in the chest compared with long-term persistence in T-and B-celldeficient mice. NK depletion reduced MAPC elimination. Because the lungs were the major uptake site after intravenous injection, intra-arterial injections were tested and found to result in more widespread biodistribution. Widespread IntroductionMultipotent adult progenitor cells (MAPCs) are a novel class of stem cells derived from adult tissues, including bone marrow, muscle, and brain. [1][2][3][4][5] MAPCs are pluripotent, and a single MAPC injected into a blastocyst contributes to all tissues, including skeletal muscle, cardiac muscle, liver, lung, intestine, central nervous system, skin, spleen, blood, and marrow. 2 Clonal MAPCs are able to differentiate in vitro into various lineages of mesodermal, ectodermal, and endodermal origin and contribute to terminally differentiated tissues when postnatally grafted. [1][2][3][4][5] This capacity is enhanced during injury, 2 suggesting a possible role for MAPCs in the regeneration of tissues injured by chemotherapy or radiation during conditioning for hematopoietic stem cell transplantation.For any clinical application of MAPCs, it is critical to understand the mechanisms that can lead to immune rejection of the infused cells. Because undifferentiated MAPCs express low levels of major histocompatibility complex (MHC) class I, MAPCs may be ideal targets for NK cell-mediated killing. If so, NK-cell resistance may serve as a barrier to the infusion of undifferentiated MAPCs in vivo. As a part of innate immune defense, NK cells can kill infected or transformed tissues before sensitization and without restriction by MHC antigens. [6][7][8] Because NK function can influence the outcome of hematopoietic cell transplantation, 9,10 we reasoned that NK activity may have a role in MAPC homing and rejection.Other important considerations in the use of MAPCs include understanding the host factors that might affect in vivo MAPC biodistribution and persistence. Therefore, we analyzed the role of MAPCs as targets of immune response as a function of engraftment and persistence of infused MAPCs using a 2-reporter gene system with red fluorescence protein derived from Discosoma coral (DsRed2) 11 and firefly luciferase. 12 Donor MAPC-derived optical signatures of fluorescent (DsRed2...

Autologous Bone Marrow Mesenchymal Stem Cell Therapy in the Subacute Stage of Traumatic Brain Injury by Lumbar Puncture

“…29 An initial drawback of intravenous application is the large proportion of first-pass pulmonary sequestration. 30 Intra-arterial administration offers a method to further localize the placement of stem cells. However, recent investigation has shown that intracarotid infusion of MSCs induces ischemic stroke.…”

Cell therapies for traumatic brain injury

“…Animals treated intravenously were found to have reduced motor and neurological severity score deficits. 41 The administration of bone marrow-derived progenitor cells intraarterially, as opposed to intravenously, has been shown to lead to a significantly greater biodistribution in other laboratories, 72 but this could also lead to the development of cell emboli, decreasing blood flow. 16 After the success of the acute therapy, Chopp and coworkers subsequently reported that MSC therapy 1 week after TBI also led to long-term functional recovery (3 months after treatment) and that the cells remained in the brain at 3 months.…”

Scrambling the Egg Origin Dogma

“…These antibodies shut down T-lymphocyte responses, which are critical for long-term immunity and rejection of transplants. Since the ability of multipotent adult progenitor cells to survive after a transplant is diminished by the persistence and activity of T and B cells [6], Tilly's use of additional immunosuppressants may have favored survival and differentiation of bone marrow stem cells in the ovary. The bone marrow transplants themselves were not equivalent.…”

“…While Wagers' lab used whole bone marrow, Tilly's laboratory used a fraction of pluripotent bone marrow cells that was enriched for germline markers and lacked hematolymphoid commitment, which may have favored engraftment of transplanted cells in the ovary. Finally, the routes of bone marrow injection, which can affect engraftment of marrow cells [6], also differed in that Wagers used retro-orbital injection and Tilly used intravenous tail injection. This difference in injection sites could also explain why Wagers observed low-level hematolymphoid chimerism in the bone marrow recipients.…”