Current progress in use of adipose derived stem cells in peripheral nerve regeneration

Table 1 Summary of seddon and sunderland classifications following peripheral nerve injury adapted from[98]

Sunderland	Seddon	Injury	Neurosensory impairment	Recovery potential
I	Neuropraxia	Intrafascicular oedema, conduction block Segmental demyelination	Neuritis, paraesthesia Neuritis, paraesthesia	Ful (1-7 d) Full (1-2 mo)
II III IV	Axonotmesis	Axons severed, endoneurial tube intact Endoneurial tube torn Only epineurium intact	Paraesthesia, episodic dysesthesia Paraesthesia Hypoaesthesia, dysaesthesia neuroma	Full (2-4 mo) Slow, Incomplete (12 mo) Neuroma
V	Neurotmesis	Loss of continuity	Anaesthesia, extreme pain and neuroma formation	None
VI		As per V	As per V	Nil

Table 2 Table of various neuron markers their distributions and function adapted from[99]

Marker	Distribution	Protein function
GFAP	Mature cells of glial origin	Specifically found in astroglial cells
MAP 2	Mature marker of neurones	Thought to be involved in microtubule assembly during neurogenesis
Nestin	Developing nervous system, myogenic, endothelial and hepatic cells	Intermediate filament protein expressed in multiple tissues
NF-70	Most PNS neurones	Structural protein supporting large axons and synapses
NSE	Early neuronal marker	Three variants: α, β, γ with only the γ isoenzyme expressed in neuronal tissue
S100	Cytoplasm of SCs, astrocytes and astrogliosis	Non-specific cell marker involved in multiple cell processes including cell cycle progression and differentiation
Synaptophisin	Brain synaptic vesicles	Directs vesicle associated membrane protein-2 to intracellular compartments
TAU	Axons	βNeuronal microtubule associated protein stabilising microtubules and link to signalling pathways to cytoskeleton
βIII-tubulin	Central and peripheral nervous system axons	β tubulins heterodimerize to form microtubules involved in axon guidance

GFAP: Glial fibrillary acid protein; MAP2: Microtubule associated protein-2; NSE: Neuron specific enolase; PNS: Peripheral nervous system; SCs: Schwann cells.

Table 3 Comparision the different methods of chemical differentiation of adipose derived stem cells

Nerve differentiation chemicals	Histochemical markers positive	Ref.
B27/bFGF/EGF	MAP2, β-III tubulin, S-100, GFAP, Nestin,	[19,21,42-45,47]
IBMX/dexamethasone/insulin/indomethacin	S100, GFAP	[94]
β-mercaptoethanol/butylated hydroxanisole/retinoic acid/EGF/bFGF	GFAP, Nestin, β-III tubulin, NSE, TAU, MAP2 and Synaptophisin	[40]
β-mercaptoethanol/retinoic acid/PDGF/bFGF/forskolin/GGF-2	GFAP, S100	[41,58,59,95]

GFAP: Glial fibrillary acid protein; MAP2: Microtubule associated protein-2; bFGF: Basic fibroblast growth factor; NSE: Neuron specific enolase; EGF: Epidermal growth factor; IBMX: Isobutylmethylxanthine; PDGF: Platelet derived growth factor; GGF-2 glial growth factor-2.

Table 4 Animal studies modelling adipose derived stem cells and conduits for peripheral regeneration

Animal models	Details	Measured outcomes	Ref.
Rat	Polycaprolactone conduit for 6 mm nerve gap	SNI, nerve thickness	[56]
Rat	Fibrin conduit 10 mm nerve gap	Axon regeneration	[42]
Rat	Polyhydroxybutyrate conduit 10 mm nerve gap	Axon regeneration	[59]
Mouse	Nerve crush model and local administration ADSC ± matrigel	Axon regeneration	[48]
Rat	Decellularised vascular conduit v autogenous nerve and vascular conduits containing ADSC	Axon regeneration, nerve conduction velocity	[90]
Rat	Silastic conduit for 13 mm nerve gap	SNI, EPT, sensory nerve function	[57]
Rat	Silicon conduit ± collagen or ADSCs	Axon regeneration, nerve conduction velocity	[100]
Rat	Nerve crush model with systemic injection of ADSC	Axon regeneration, motor recovery	[68]
Rat	Genipin-Gelatin-Tricalcium phosphate conduit 10 mm nerve gap	SNI	[92]
Rat	ADSC injected into repaired chronic denervated nerve	Axon regeneration, PFI	[89]
Rat	Microporous conduit for 15 mm nerve gap	Motor recovery	[60]
Rat	Fibrin conduit for 10 mm nerve gap	Motor recovery, GAP-43 expression in dorsal root ganglion	[58]
Dog	Polytetrafluoroethylene tube and alginate hydrogel l 7 mm nerve gap	Axon regeneration	[51]

ADSC: Adipose derived stem cell; SNI: Sciatic nerve index; GAP-43: Growth associated protein.