Adipose-derived stromal cells: Their identity and uses in clinical trials, an update

Table 1 Differentiated phenotype given rise from adipose-derived stromal cell and interactive effects of these cells with immune and cancer cells

Phenotype given rise in in vitro system	Ref.
Classic mesenchymal phenotype (adipocyte, osteoblast, chondrocyte)	[1]
Hematopoietic supporting cells	[25]
Other phenotypes	Vascular cells (Smooth-muscle cells, Endothelial)[16]
	Neurones[1]
	Cardiomyocyte and skeletal cells in the required presence of 5 azacytidine[16]
Modulation of inflammation and immune suppressive functions	Rheumatoid arthritis[31]
	GVH[30]
	Autoimmune encephalomyelitis[32]
Anti-cancer effect	Tumor progression inhibition[34]
Pro-cancer effects	Tumor progression growth[35,37]

Table 2 The different steps for a clinical trialand cancer cells

Steps of clinical trial	Elements of discussion
Design	Autologous
	Immunocompatibility
	Lag of time between fat sampling and delivery
	Amount of cells
	Allogenic
	Histocompability issue
	If bank, ready to use treatment
	Inclusion criteria
	Too broad: leads to wrong conclusions associated with great variability and independent parameters,
	Too restricted: enrolment difficulties associated with non relevant and inadequate parameters
	Exclusion criteria
	Too broad: enrolment difficulties associated with non relevant and inadequate parameters
	Too restricted: risks of adverse side effects associated with interactions between transplanted cells and undesirable context
	Number of patients: statistically defined
	Objective and well-established criteria of safety and efficacy
	Uni or multicenter analysis
	Standardization of procedures between centers
	Efficiency of enrolment
Sampling	Liposuction:
	Local anesthesia
	Fat depot
	Technique (no ultra-sound)
	Anti-coagulant
Culture	Opened or closed system
	Bovine or human-derived products
	Number of passages
	Quality and Safety control
	Release criteria
Injection	iv
	Poorly invasive but large distribution and mostly trapped in lung
	im or intra tissue
	More invasive
	More restricted localization
	Pressure challenge for adipose-derived stromal cells
Monitoring of the tolerance and the safety	Criteria: pain, wound healing, inflammation, immunology, tumor
	Kinetics for analysis
	Short and long term safety
Monitoring of the results	Objective criteria, standardisation of procedures
Analysis of the results	Adequate statisitic
	Stick to primary and secondary aims

Table 3 Clincial trials using stromal vascular fraction

Clinical trials with SVF	Design	Results	Ref
Traumatic calvaria defect	Autologous SVF + fibrin glue: case report	Success	{Lendeckel, 2004 #483}
Breast reconstruction after lumpectomy	Autologous fat + autologous SVF. No arm control	Cysts and Microcalcifications (4/70 patients)	{Yoshimura, 2008 #481} {Yoshimura, 2008 #481}
	Autologous fat + autologous SVF, phase IV		NCT00616135*
Lipodystrophy I	Autologous SVF + fat	recruiting	NCT00715546*
	Phase I
Non revascularizable myocardium	Autologous SVF	ongoing	NCT00426868*
	Injection into the left ventricle
Treatment of Pts With ST-Elevation Myocardial Infarction	Autologous SVF, Phase I	Ongoing	NCT00442806*
	Injection into the left ventricle
	Autologous SVF, 2 doses against placebo, Phase II, III, Intracoronary injection	Not yet open	NCT01216995*
Diabetes I	“Activated” autologous SVF, phase I/II	recruiting	NCT00703599*
	iv administration
Diabetes II	“Activated” autologous SVF, phase I/II	recruiting	NCT00703612*
Liver cirrhosis	Autologous SVF	Suspended	NCT00913289*
	Intrahepatic arterial administration	suspended	NCT01062750

The clinical trials that are indexed in this table were retrieved using adipose, derived and stem in clinicaltrial and PubMed websites. As discussed in the text, there is some confusion about the use of the term adipose-derived stroma/stem cells. This term should be restricted to cultured mesenchymal stem cells. In fact, it can recover the use of the crude and strongly heterogeneous stroma fraction just after its recovery after fat digestion. The trials listed in this table correspond to the use of such fraction (*identifier on Clinicaltrials website: *http://clinicaltrials.gov/ct2/results?term=adipose+derived+cells). SVF: Stromal vascular fraction.

Table 4 Clincial trials using adipose-derived stromal cell

Clinical trials with ADSC	Design	Results	Ref
Maxillary reconstruction	Autologous ADSC case report	Success	{Mesimaki, 2009 #480}
Cryptoglandular origin fistula with or without Crohn’s disease	Autologous ADSC phase I/II intra-tissue	ADSCs more effective (P = 0.001). Recurrence rate with ADSC = 17.6%	{Garcia-Olmo, 2008 #451; Garcia-Olmo, 2009 #449}
	Autologous ADSC	Ongoing, not recruiting	NCT00115466*
	Phase II, 2 arms (fibrin glue, fibrin glue + ADSC)
Crohn’s disease fistula	Autologous ADSC, phase I and II	Phase I, complete	NCT00992485*
		Phase II recruiting	NCT01011244*
	Autologous ADSC, phase I	Phase I/II recruiting	NCT01157650*
	Allogenic ADSC: phase I/II	recruiting	NCT00999115*
	20 × 106 then 40 × 106
Complex Perianal Fistulas not associated to Crohn’s disease	Autologous ADSC, phase III three arms (fibrine, ADSC, fibrin glue + ADSC; 20 × 106 then 40 × 106 when no effect)	Completed (214 enrolled patients)	NCT00475410*
	Long term safety	Recruiting	NCT01020825*
Depressed Scar	Autologous ADSC predifferentiated towards adipocyte, phase II, III	Complete	NCT00992147*
Chronic critical limb Ischemia	Autologous ADSC, phase I	Recruiting	NCT01211028*
	im 100 × 106
Chronic critical limb Ischemia in diabetic patients	Autologous ADSC, phase I/II	Recruiting	NCT01079403*
	iv administration
Fecal incontinence	Autologous ADSC, phase I	Recruiting	NCT01011686*
GVHD	Autologous ADSC	4/5 alive (after a median follow-up of 40 mo)	{Fang, 2007 #469}
	iv 106/kg
	Autologous ADSC	Recruiting	NCT01222039
	Three arms no administration, iv 106/kg or 3 × 106/kg
Secondary Progressive Multiple Sclerosis	Autologous ADSC phase I/II	Recruiting	NCT01056471*
	3 arms (iv 106 and 4 × 106/kg against no intervention)

The clinical trials that are indexed in this table were retrieved using adipose, derived and stem in clinicaltrial and Pubmed websites. As discussed in the text, there is some confusion about the use of the term adipose-derived stroma/stem cells that can be used for crude SVF. This term should be restricted to cultured adipose derived mesenchymal stem cells and the table lists the trials using such cells (*identifier on Clinicaltrials website: *http://clinicaltrials.gov/ct2/results?term=adipose+derived+cells). ADSC: Adipose-derived stromal cell; GVHD: Graft-versus-host disease.