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2014 ; 3
(12
): 1444-50
Nephropedia Template TP
Davis TA
; Anam K
; Lazdun Y
; Gimble JM
; Elster EA
Stem Cells Transl Med
2014[Dec]; 3
(12
): 1444-50
PMID25411475
show ga
Amputations and unsalvageable injuries with devastating tissue loss are common in
the combat wounded. Reconstructive transplantation in the civilian setting using
vascular composite allotransplants (VCAs) with multiple tissues (skin, muscle,
nerve, bone) combined with long-term multidrug immunosuppression has been
encouraging. However, skin rejection remains a critical complication.
Adipose-derived stromal/stem cells (ASCs) are easily obtained from normal
individuals in high numbers, precluding ex vivo expansion. The reparative
function and paracrine immunomodulatory capacity of ASCs has gained considerable
attention. The present study investigated whether ASCs facilitate long-term skin
allograft survival. ASCs were isolated from fresh human subcutaneous adipose
lipoaspirate. Full-thickness skin grafts from BALB/c mice were transplanted onto
the dorsal flanks of C57BL/6 mice treated with five doses of anti-CD4/CD8
monoclonal antibodies (10 mg/kg) on days 0, +2, +5, +7, and +14 relative to skin
grafting. A single nonmyeloablative low dose of busulfan (5 mg/kg) was given on
day +5. Seven days after skin transplantation, ASCs (3×10(6)) were infused i.v.
with or without donor bone marrow cells (BMCs; 5×10(5)). ASC+BMC coinfusion with
minimal conditioning led to stable lymphoid and myeloid macrochimerism, deletion
of alloreactive T cells, expansion of regulatory T cells, and long-term allograft
survival (>200 days). ASCs constitutively produced high levels of
anti-inflammatory/immunoregulatory factors such as prostaglandin E2, indoleamine
2,3-dioxygenase, APO-1/Fas (CD95), and programmed cell death-1 ligand-2. These
findings serve as a foundation for developing a translational advanced VCA
protocol, embodying both ASCs and low-dose donor BMCs, in nonhuman primates, with
the goal of enhancing functional outcomes and eliminating the complications
associated with long-term immunosuppression.
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