Mesenchymal Stem Cells as a Treatment for Peripheral Arterial Disease: Current Status and Potential Impact of Type II Diabetes on Their Therapeutic Efficacy

Abstract

Mesenchymal stem cells (MSCs), due to their paracrine, transdifferentiation, and immunosuppressive effects, hold great promise as a therapy for peripheral arterial disease. Diabetes is an important risk factor for peripheral arterial disease; however, little is known of how type II diabetes affects the therapeutic function of MSCs. This review summarizes the current status of preclinical and clinical studies that have been performed to determine the efficacy of MSCs in the treatment of peripheral arterial disease. We also present findings from our laboratory regarding the impact of type II diabetes on the therapeutic efficacy of MSCs neovascularization after the induction of hindlimb ischemia. In our studies, we documented that experimental type II diabetes in db/db mice impaired MSCs’ therapeutic function by favoring their differentiation towards adipocytes, while limiting their differentiation towards endothelial cells. Moreover, type II diabetes impaired the capacity of MSCs to promote neovascularization in the ischemic hindlimb. We further showed that these impairments of MSC function and multipotency were secondary to hyperinsulinemia-induced, Nox4-dependent oxidant stress in db/db MSCs. Should human MSCs display similar oxidant stress-induced impairment of function, these findings might permit greater leverage of the potential of MSC transplantation, particularly in the setting of diabetes or other cardiovascular risk factors, as well as provide a therapeutic approach by reversing the oxidant stress of MSCs prior to transplantation.

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Abbreviations

(A):

Autologous

(Al):

Allogenic

ABI:

Ankle-brachial index

AE:

Adverse events

AFS:

Amputation-free survival

CLI:

Critical limb ischemia

CL:

Contralateral leg

DSA:

Digital subtraction angiography

MRA:

Magnetic resonance angiography

PS:

Perfusion scintigraphy

QoL:

Quality of life survey

RP:

Rest pain

TAO:

Thromboangiitis obliterans

TcPO2 :

Transcutaneous oxygen pressure

TTF:

Time to treatment failure

WH:

Wound healing

WT/D:

Pain free walking time/distance

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Acknowledgment

The authors acknowledge financial support from grant HL75353 from the National Institute for Heart, Lung, and Blood (to L.M.M.).

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The authors declare no potential conflicts of interest.

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Correspondence to Louis M. Messina.

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Yan, J., Tie, G., Xu, T.Y. et al. Mesenchymal Stem Cells as a Treatment for Peripheral Arterial Disease: Current Status and Potential Impact of Type II Diabetes on Their Therapeutic Efficacy. Stem Cell Rev and Rep 9, 360–372 (2013). https://doi.org/10.1007/s12015-013-9433-8

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Keywords

  • Mesenchymal stem cells
  • Peripheral arterial disease
  • Oxidative stress
  • Limb ischemia