Phase I trial: the use of autologous cultured adipose-derived stroma/stem cells to treat patients with non-revascularizable critical limb ischemia.
OBJECTIVE
Non-revascularizable critical limb ischemia (CLI) is the most severe stage of peripheral arterial disease, with no therapeutic option. Extensive preclinical studies have demonstrated that adipose-derived stroma cell (ASC) transplantation strongly improves revascularization and tissue perfusion in ischemic limbs. This study, named ACellDREAM, is the first phase I trial to evaluate the feasibility and safety of intramuscular injections of autologous ASC in non-revascularizable CLI patients.


METHODS
Seven patients were consecutively enrolled, on the basis of the following criteria: (i) lower-limb rest pain or ulcer; (ii) ankle systolic oxygen pressure <50 or 70 mm Hg for non-diabetic and diabetic patients, respectively, or first-toe systolic oxygen pressure <30 mm Hg or 50 mm Hg for non-diabetic and diabetic patients, respectively; (iii) not suitable for revascularization. ASCs from abdominal fat were grown for 2 weeks and were then characterized.


RESULTS
More than 200 million cells were obtained, with almost total homogeneity and no karyotype abnormality. The expressions of stemness markers Oct4 and Nanog were very low, whereas expression of telomerase was undetectable in human ASCs compared with human embryonic stem cells. ASCs (10(8)) were then intramuscularly injected into the ischemic leg of patients, with no complication, as judged by an independent committee. Trans-cutaneous oxygen pressure tended to increase in most patients. Ulcer evolution and wound healing showed improvement.


CONCLUSIONS
These data demonstrate the feasibility and safety of autologous ASC transplantation in patients with objectively proven CLI not suitable for revascularization. The improved wound healing also supports a putative functional efficiency.
Service de médecine vasculaire, Pôle cardiovasculaire et métabolique, Centre hospitalo-universitaire de Toulouse, Toulouse, France; Université de Toulouse III, Paul Sabatier, Toulouse, France.
Alessandra
A
Bura
CNRS, Université Toulouse III, UPS UMR5273 STROMAlab, Toulouse, France; EFS (Etablissement Français du Sang), STROMAlab, Toulouse, France; Inserm U1031 STROMAlab, Toulouse, France; Université Toulouse III, UPS UMR5273 STROMAlab, Toulouse, France.
Valerie
V
Planat-Benard
EFS (Etablissement Français du Sang), STROMAlab, Toulouse, France; CSA21, 7 chemin des silos, Toulouse, France.
Philippe
P
Bourin
INSERM UMRS 970, Paris Cardiovascular Research Center, Université Paris Descartes, Sorbonne Paris cité, Paris, France.
Jean-Sebastien
JS
Silvestre
Centre d'Investigation Clinique de Biothérapies de Toulouse, Toulouse cedex 9, France; Direction de la Recherche Médicale et Innovation (DRMI) du CHU de Toulouse, Toulouse cedex 9, France.
Fabian
F
Gross
Université de Toulouse III, Paul Sabatier, Toulouse, France; Service de chirurgie plastique, reconstructrice et esthétique, Centre hospitalo-universitaire de Toulouse, Toulouse, France.
Jean-Louis
JL
Grolleau
Service de chirurgie vasculaire, Pôle cardiovasculaire et métabolique, Centre hospitalo-universitaire de Toulouse, Toulouse, France.
Bertrand
B
Saint-Lebese
CNRS, Université Toulouse III, UPS UMR5273 STROMAlab, Toulouse, France; EFS (Etablissement Français du Sang), STROMAlab, Toulouse, France; Inserm U1031 STROMAlab, Toulouse, France; Université Toulouse III, UPS UMR5273 STROMAlab, Toulouse, France.
Julie-Anne
JA
Peyrafitte
CNRS, Université Toulouse III, UPS UMR5273 STROMAlab, Toulouse, France; EFS (Etablissement Français du Sang), STROMAlab, Toulouse, France; Inserm U1031 STROMAlab, Toulouse, France; Université Toulouse III, UPS UMR5273 STROMAlab, Toulouse, France.
Sandrine
S
Fleury
CNRS, Université Toulouse III, UPS UMR5273 STROMAlab, Toulouse, France; EFS (Etablissement Français du Sang), STROMAlab, Toulouse, France; Inserm U1031 STROMAlab, Toulouse, France; Université Toulouse III, UPS UMR5273 STROMAlab, Toulouse, France.
Melanie
M
Gadelorge
CNRS, Université Toulouse III, UPS UMR5273 STROMAlab, Toulouse, France; EFS (Etablissement Français du Sang), STROMAlab, Toulouse, France; Inserm U1031 STROMAlab, Toulouse, France; Université Toulouse III, UPS UMR5273 STROMAlab, Toulouse, France.
Marion
M
Taurand
CNRS, Université Toulouse III, UPS UMR5273 STROMAlab, Toulouse, France; EFS (Etablissement Français du Sang), STROMAlab, Toulouse, France; Inserm U1031 STROMAlab, Toulouse, France; Université Toulouse III, UPS UMR5273 STROMAlab, Toulouse, France.
Sophie
S
Dupuis-Coronas
Université de Toulouse III, Paul Sabatier, Toulouse, France; Service de chirurgie cardiovasculaire, Pôle cardiovasculaire et métabolique, Centre hospitalo-universitaire de Toulouse, Toulouse, France.
Bertrand
B
Leobon
CNRS, Université Toulouse III, UPS UMR5273 STROMAlab, Toulouse, France; EFS (Etablissement Français du Sang), STROMAlab, Toulouse, France; Inserm U1031 STROMAlab, Toulouse, France; Université Toulouse III, UPS UMR5273 STROMAlab, Toulouse, France. Electronic address: louis.casteilla@inserm.fr.
Louis
L
Casteilla
D000273:Adipose Tissue / Q000166:cytology*; D000328:Adult; D053687:Adult Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D000368:Aged; D000369:Aged, 80 and over; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D005121:Extremities / Q000098:blood supply / Q000473:pathology* / Q000637:transplantation; D005240:Feasibility Studies; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007273:Injections, Intramuscular; D007511:Ischemia / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D000071317:Nanog Homeobox Protein; D018919:Neovascularization, Physiologic; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D058729:Peripheral Arterial Disease / Q000628:therapy*; D033581:Stem Cell Transplantation; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D016896:Treatment Outcome
D018398:Homeodomain Proteins; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human
ASC; CLI; adipose tissue; cell therapy; mesenchymal stromal cells