p21cip/WAF is a key regulator of radiation damage in mesenchymal derived tissues
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Transcript of p21cip/WAF is a key regulator of radiation damage in mesenchymal derived tissues
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S84 Surgical Forum Abstracts J Am Coll Surg
ors received skin grafts, rejecting 3rd party while accepting same-onor skin �30 days (p�0.05).
ONCLUSIONS: Short-course CD200 with ALS�CsA prolongsllograft survival in a highly immunogenic model without long-termmmunosuppression. CD200-induced immunoregulation occurshrough increased Tregs, and early cellular infiltration foretells laterejection. This model provides unique evidence for a link betweenD200 and tolerance in CTA.
21cip/WAF is a key regulator of radiation damagen mesenchymal derived tissuesomer Avraham MD, Marc Soares MD, Jamie C Zampell MD,lan Yan MD, Sanjay V Daluvoy MD, Babak J Mehrara MD, FACSemorial Sloan-Kettering Cancer Center, New York, NY
NTRODUCTION: We have previously shown that mesenchymal stemells (MSCs) are sensitive to radiation in terms of cellular differentiationotential and that the expression of p21, a cell cycle regulator is increasedfter radiation. The purpose of these studies was to determine the role of21 in the regulation of MSC function after radiation injury and iden-ify the mechanisms responsible for long-term tissue injury.
ETHODS: We irradiated p21 knockout (p21-/-) and wild typeWT) mice and then determined the long-term deleterious effects ofhis intervention on mesenchymal derived tissues and isolated MSCsoth in vivo and in vivo.
ESULTS: p21 expression was chronically elevated �200-fold in irra-iated tissues. Loss of p21 function resulted in a �4-fold increase in theumber of skin MSCs remaining after radiation. p21-/- mice exhibitedignificantly less radiation damage (6-fold less scarring, 40% increasedrowth potential, and 4-fold more hypertrophic chondrocytes in thepiphyseal plate; p�0.01). Irradiated isolated p21-/- MSCs had 4-foldncreased potential for bone or fat differentiation, 4-fold greater prolif-ration rate, and 7-fold lower senescence as compared to WT MSCsp�0.01). Ectopic expression of p21 in p21-/- cells decreased prolifera-ion and differentiation and recapitulated the WT phenotype.
ONCLUSIONS: Loss of p21 function markedly decreases the long-erm deleterious effects of radiation in mesenchymal derived tissues andreserves tissue derived MSCs. In addition, p21 is a critical regulator ofSC differentiation and senescence.These findings suggest that chronic
pregulation of p21 expression by local tissue stem cells after irradiationauses impaired tissue regeneration and turnover.
ffects of electro-conductive biopolymer on axonegeneration across a peripheral nerve interfaceiya Baghmanli MD, Melanie Urbanchek PhD, Bong S Shim PhD,enjamin Wei MD, David C Martin PhD,illiam M Kuzon Jr MD, PhD, FACS, Paul S Cederna MD, FACSniversity of Michigan, Ann Arbor, MI
NTRODUCTION: Our long-term objective is to create a peripheralerve interface (PNI) to functionally connect native nerve to inor-anic wires, permitting signal transmission of afferent-sensory- and
fferent-motor- signals. We incorporated the electrochemical poly- ber 3,4-polyethylenedioxythiophene (PEDOT) into the PNI toower the electrical impedance and improve the signal-to-noise ratiot the biotic-abiotic interface. The purpose of this study is to deter-ine the impact of PEDOT on axon regeneration.
ETHODS: Rats were assigned to 1 of 5 groups (n�8/group) basedn peripheral nerve (PN) gap reconstruction materials. Grafts were5mm. Groups were: 1) PEDOT (reconstruction with PEDOThemically acellularized PN); 2) SHAM (dissection of PN but noerve lesions); 3) AUTO (reconstruction with autograft); 4) ANreconstruction with chemically acellularized PN), and 5) NORAFT (PN gap not reconstructed). After 90 days of recovery, nerve
onduction (NC) and muscle contractile force data were measured.
ESULTS: NC latency and electrical activity for PEDOT groupere indifferent from the AUTO group, the “gold standard” forerve gap reconstruction. However, reinnervated muscle of theEDOT group did not recover as much force capacity as the AUTOr AN groups. (Table 1) This discrepancy between good NC yetoorer muscle force for the PEDOT group when compared with theUTO group indicates that PEDOT maintains signal conduction to
he muscle but interferes with muscle reinnervation.
ummary of Statistical Data by Surgical Groups
ependentariables
Independent variable
SHAM(Control) AUTO AN PEDOT NO GRAFT
n�8 n�8 n�8 n�8 n�8
atency (msec) 1.33�0.17 1.52�0.16* 2.1�0.36* 0.5�0.47 No record
mplitude (mV) 19.17�5.43 8.06�2.89* 6.43�3.37* 6.89�7.85* No record
ax. isometricmuscleforce (mN)
2868.63�798.5 1591.68�520.194* 659.32�659.9* 66.34�142.3* No record
ndependent variable indicates type of reconstruction implemented to the 15 mm length nerve gap.alues are mean�SD.Indicates statistical difference from SHAM, p�0.05. AUTO- autograft, AN- acellular peroneal nerve,EDOT- PEDOT chemically polymerized acellular peroneal nerve
ONCLUSIONS: In a nonmetallic peripheral nerve interface, thelectro-conductive polymer-PEDOT maintains real time signal transferut may interfere with axon regeneration. Ongoing histology will ad-ress axon growth in the graft. (The views expressed in this work arehose of the authors and do not necessarily reflect official Army policy.his work was supported by the Department of Defense Multidisci-linary University Research Initiative (MURI) program administered byhe Army Research Office under grant W911NF0610218.)
s lacunocanalicular flow the transducer ofechanical tension stress to osteogenesis inistraction?dward H Davidson MA MBBS, Steven M Sultan BA,arag Butala MD, Denis Knobel MD, John Paul Tutela MD,rlando Canizares MD, I Janelle Wagner MD, Lukasz Witek BS,in Hu MD, Stephen M Warren MD, FACSew York University, New York, NY
NTRODUCTION: Our hypothesis is that the tension stress of acti-ation increases lacunocanalicular flow and upregulates the mech-notransductive osteogenic pathway. Furthermore, we hypothesizemproving vascularization by endothelial progenitor cell (EPC) mo-
ilization enhances lacunocanalicular flow in the consolidation pe-