**2.1. Spinal cord injury pathological events and timing sequence**

Spinal cord injury (SCI) is often mentioned among the first conditions for which stem cells may provide a new therapy. While recent decades have brought significant improvements in rescuing neuronal activity after SCI at preclinical phases testing several individual approaches, translation to the clinic still remains inefficiently explored. Management for SCI efficient treatment is a difficult task by the intrinsic nature of the pathological cascade of events that makes the SCI a dynamic and progressive disorder. The sentence "Time is spine" defines the crucial importance of timing to rapidly diagnose patients and implement neuroprotective interventions during the acute injury phase (≤2 h) in order to diminish the devastating effects of the secondary phase of the injury (≥2–48 h) which are known to be key determinants of the final extent of neurological deficits. The secondary injury leads to necrosis and/or apoptosis of neurons and glial cells, such as oligodendrocytes, which can lead to demyelination and the loss of neural circuits. Later, in a subacute phase (2–4 days after injury), further ischemia occurs owing to ongoing edema, vessel thrombosis, and vasospasm. Persistent inflammatory cell infiltration causes further cell death and formation of very toxic cystic microcavities over time. Astrocytes, fibroblast, and pericytes proliferate and deposit extracellular matrix molecules into the perilesional area in the already intermediate and chronic phases, few weeks after SCI, when axons continue degenerating (**Figure 1a**) [11].

Spontaneous regeneration during and after having reached the chronic stage occurs due to the neuroplasticity capacity of the central nervous system (CNS); however, very limited gain of function is obtained decreasing advancing age, attributed to both extrinsic and intrinsic factors that modulate further onset, severity, and progression of the injury [12]. The cumulative myelin-associated protein anchorage to myelin sheet debris, in and around the epicenter of the injury, has a strong inhibitory nature. Nogo-A (reticulon-4 isoform A) and myelin-associated glycoprotein (MAG), among other myelin-associated proteins, bind to NOGO receptors to activate the GTPase Rho A, which activates Rho-associated protein kinase (ROCK), a regulator of further downstream effectors, leading to apoptosis and growth-cone collapse of regenerating axons involving neurite retraction [13–17]. Additional external barriers are potently adding to the inhibition of regeneration like the hypertrophic astrocytes and the reactive chemical scar with a number of axonal growth inhibitory chondroitin sulfate proteoglycans (CSPGs) [18].

The chronic SCI repair demands an intensive effort to overcome the impediments and enhance the intrinsic axon regeneration involving an efficient anatomical reorganization [19, 20]. Fortunately, although long distances for axonal reconnection or spared degenerated tracts are normally required, involving a long-term process (a rate of 1 mm/month for axon growth is estimated), it has been shown that as little as 10% of particular tracts can subserve substantial function [19, 20]. This in fact allows hypothesizing for a real recovery, mediated by bridging and partially reconnecting the spared axons allowing subsequent plasticity. Additionally, both, humans and rats, can regain a degree of function after incomplete injury, thought to be mostly due to local structural rearrangements, such as collateral sprouting from remaining axons in the gray matter, rather than by long-distance regeneration of axons in the white matter (**Figure 1b**) [21].
