Cryopreserved Mesenchymal Stromal Cells Are Susceptible to T-Cell Mediated Apoptosis Which Is Partly Rescued by IFNγ Licensing.
Abstract
We have previously demonstrated that cryopreservation and thawing lead to altered
Mesenchymal stromal cells (MSC) functionalities. Here, we further analyzed MSC's fitness
post freeze-thaw. We have observed that thawed MSC can suppress T-cell proliferation
when separated from them by transwell membrane and the effect is lost in a MSC:T-cell
coculture system. Unlike actively growing MSCs, thawed MSCs were lysed upon coculture
with activated autologous Peripheral Blood Mononuclear Cells (PBMCs) and the lysing
effect was further enhanced with allogeneic PBMCs. The use of DMSO-free cryoprotectants
or substitution of Human Serum Albumin (HSA) with human platelet lysate in freezing
media and use of autophagy or caspase inhibitors did not prevent thaw defects. We
tested the hypothesis that IFNγ prelicensing before cryobanking can enhance MSC fitness
post thaw. Post thawing, IFNγ licensed MSCs inhibit T cell proliferation as well as
fresh MSCs and this effect can be blocked by 1-methyl Tryptophan, an Indoleamine 2,3-dioxygenase
(IDO) inhibitor. In addition, IFNγ prelicensed thawed MSCs inhibit the degranulation
of cytotoxic T cells while IFNγ unlicensed thawed MSCs failed to do so. However, IFNγ
prelicensed thawed MSCs do not deploy lung tropism in vivo following intravenous injection
as well as fresh MSCs suggesting that IFNγ prelicensing does not fully rescue thaw-induced
lung homing defect. We identified reversible and irreversible cryoinjury mechanisms
that result in susceptibility to host T-cell cytolysis and affect MSC's cell survival
and tissue distribution. The susceptibility of MSC to negative effects of cryopreservation
and the potential to mitigate the effects with IFNγ prelicensing may inform strategies
to enhance the therapeutic efficacy of MSC in clinical use. Stem Cells 2016;34:2429-2442.
Type
Journal articleSubject
LungT-Lymphocytes
T-Lymphocytes, Cytotoxic
Mesenchymal Stem Cells
Animals
Mice, Inbred C57BL
Humans
Caspases
Cryopreservation
Immunosuppression
Lymphocyte Activation
Cell Communication
Apoptosis
Cell Proliferation
Cell Survival
Cell Degranulation
Heat-Shock Response
Freezing
Autophagy
Interferon-gamma
Polymerization
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https://hdl.handle.net/10161/21185Published Version (Please cite this version)
10.1002/stem.2415Publication Info
Chinnadurai, Raghavan; Copland, Ian B; Garcia, Marco A; Petersen, Christopher T; Lewis,
Christopher N; Waller, Edmund K; ... Galipeau, Jacques (2016). Cryopreserved Mesenchymal Stromal Cells Are Susceptible to T-Cell Mediated Apoptosis
Which Is Partly Rescued by IFNγ Licensing. Stem cells (Dayton, Ohio), 34(9). pp. 2429-2442. 10.1002/stem.2415. Retrieved from https://hdl.handle.net/10161/21185.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Allan Douglas Kirk
David C. Sabiston, Jr. Distinguished Professor of Surgery
I am a surgeon with interest in immune management of transplant recipients. I am particularly
interested in therapies that influence T cell costimulation pathways and adjuvant
therapies that facilitate costimulation blockade to prevent the rejection of transplanted
organs without undue suppression of protective immunity. I am also interested in understanding
how injury, such as that occurring during trauma or in elective surgery, influences
immune responses and subsequent healing following injur
Holly Lewis
House Staff
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