p21cip/WAF is a key regulator of radiation damage in mesenchymal derived tissues

1
vors received skin grafts, rejecting 3rd party while accepting same- donor skin 30 days (p0.05). CONCLUSIONS: Short-course CD200 with ALSCsA prolongs allograft survival in a highly immunogenic model without long-term immunosuppression. CD200-induced immunoregulation occurs through increased Tregs, and early cellular infiltration foretells later rejection. This model provides unique evidence for a link between CD200 and tolerance in CTA. p21cip/WAF is a key regulator of radiation damage in mesenchymal derived tissues Tomer Avraham MD, Marc Soares MD, Jamie C Zampell MD, Alan Yan MD, Sanjay V Daluvoy MD, Babak J Mehrara MD, FACS Memorial Sloan-Kettering Cancer Center, New York, NY INTRODUCTION: We have previously shown that mesenchymal stem cells (MSCs) are sensitive to radiation in terms of cellular differentiation potential and that the expression of p21, a cell cycle regulator is increased after radiation. The purpose of these studies was to determine the role of p21 in the regulation of MSC function after radiation injury and iden- tify the mechanisms responsible for long-term tissue injury. METHODS: We irradiated p21 knockout (p21-/-) and wild type (WT) mice and then determined the long-term deleterious effects of this intervention on mesenchymal derived tissues and isolated MSCs both in vivo and in vivo. RESULTS: p21 expression was chronically elevated 200-fold in irra- diated tissues. Loss of p21 function resulted in a 4-fold increase in the number of skin MSCs remaining after radiation. p21-/- mice exhibited significantly less radiation damage (6-fold less scarring, 40% increased growth potential, and 4-fold more hypertrophic chondrocytes in the epiphyseal plate; p0.01). Irradiated isolated p21-/- MSCs had 4-fold increased potential for bone or fat differentiation, 4-fold greater prolif- eration rate, and 7-fold lower senescence as compared to WT MSCs (p0.01). Ectopic expression of p21 in p21-/- cells decreased prolifera- tion and differentiation and recapitulated the WT phenotype. CONCLUSIONS: Loss of p21 function markedly decreases the long- term deleterious effects of radiation in mesenchymal derived tissues and preserves tissue derived MSCs. In addition, p21 is a critical regulator of MSC differentiation and senescence. These findings suggest that chronic upregulation of p21 expression by local tissue stem cells after irradiation causes impaired tissue regeneration and turnover. Effects of electro-conductive biopolymer on axon regeneration across a peripheral nerve interface Ziya Baghmanli MD, Melanie Urbanchek PhD, Bong S Shim PhD, Benjamin Wei MD, David C Martin PhD, William M Kuzon Jr MD, PhD, FACS, Paul S Cederna MD, FACS University of Michigan, Ann Arbor, MI INTRODUCTION: Our long-term objective is to create a peripheral nerve interface (PNI) to functionally connect native nerve to inor- ganic wires, permitting signal transmission of afferent-sensory- and efferent-motor- signals. We incorporated the electrochemical poly- mer 3,4-polyethylenedioxythiophene (PEDOT) into the PNI to lower the electrical impedance and improve the signal-to-noise ratio at the biotic-abiotic interface. The purpose of this study is to deter- mine the impact of PEDOT on axon regeneration. METHODS: Rats were assigned to 1 of 5 groups (n8/group) based on peripheral nerve (PN) gap reconstruction materials. Grafts were 15mm. Groups were: 1) PEDOT (reconstruction with PEDOT chemically acellularized PN); 2) SHAM (dissection of PN but no nerve lesions); 3) AUTO (reconstruction with autograft); 4) AN (reconstruction with chemically acellularized PN), and 5) NO GRAFT (PN gap not reconstructed). After 90 days of recovery, nerve conduction (NC) and muscle contractile force data were measured. RESULTS: NC latency and electrical activity for PEDOT group were indifferent from the AUTO group, the “gold standard” for nerve gap reconstruction. However, reinnervated muscle of the PEDOT group did not recover as much force capacity as the AUTO or AN groups. (Table 1) This discrepancy between good NC yet poorer muscle force for the PEDOT group when compared with the AUTO group indicates that PEDOT maintains signal conduction to the muscle but interferes with muscle reinnervation. Summary of Statistical Data by Surgical Groups Dependent Variables Independent variable SHAM(Control) AUTO AN PEDOT NO GRAFT n8 n8 n8 n8 n8 Latency (msec) 1.330.17 1.520.16* 2.10.36* 0.50.47 No record Amplitude (mV) 19.175.43 8.062.89* 6.433.37* 6.897.85* No record Max. isometric muscle force (mN) 2868.63798.5 1591.68520.194* 659.32659.9* 66.34142.3* No record Independent variable indicates type of reconstruction implemented to the 15 mm length nerve gap. Values are meanSD. *Indicates statistical difference from SHAM, p0.05. AUTO- autograft, AN- acellular peroneal nerve, PEDOT- PEDOT chemically polymerized acellular peroneal nerve CONCLUSIONS: In a nonmetallic peripheral nerve interface, the electro-conductive polymer-PEDOT maintains real time signal transfer but may interfere with axon regeneration. Ongoing histology will ad- dress axon growth in the graft. (The views expressed in this work are those of the authors and do not necessarily reflect official Army policy. This work was supported by the Department of Defense Multidisci- plinary University Research Initiative (MURI) program administered by the Army Research Office under grant W911NF0610218.) Is lacunocanalicular flow the transducer of mechanical tension stress to osteogenesis in distraction? Edward H Davidson MA MBBS, Steven M Sultan BA, Parag Butala MD, Denis Knobel MD, John PaulTutela MD, Orlando Canizares MD, I Janelle Wagner MD, Lukasz Witek BS, Bin Hu MD, Stephen MWarren MD, FACS New York University, New York, NY INTRODUCTION: Our hypothesis is that the tension stress of acti- vation increases lacunocanalicular flow and upregulates the mech- anotransductive osteogenic pathway. Furthermore, we hypothesize improving vascularization by endothelial progenitor cell (EPC) mo- bilization enhances lacunocanalicular flow in the consolidation pe- S84 Surgical Forum Abstracts J Am Coll Surg

Transcript of p21cip/WAF is a key regulator of radiation damage in mesenchymal derived tissues

Page 1: p21cip/WAF is a key regulator of radiation damage in mesenchymal derived tissues

vd

CaitrC

piTAM

Icpapt

M(tb

Rdnsgeie(t

CtpMuc

ErZBWU

Inge

mlam

Mo1cn(Gc

RwnPopAt

S

DV

L

A

M

IV*P

CebdtTpt

ImdEPOBN

Ivai

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- b

er 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-