**6. Why mesenchymal stem cell functions do not soundly shift these cells toward clinic yet?**

It is well established that, despite promising preclinical findings about mesenchymal stem cells, clinical trials failed to be impressive in SCI treatment and are still away from obtaining behavioral and functional improvement and repairing neural circuits totally [88].

Regarding the previous researches, studies using animal models are usually performed by applying standardized protocols of lesions, treatments, and specific timings of transplantation in each group of investigation [89]. However, these conditions are often incomparable with human subjects because timing and therapies are dependent on emergency setting and many variables such as lesion site damage at the cord [90]. Most of animal studies are necessarily done with rodents such as mice and rat, and, despite many anatomical or behavioral similarities, clinical trials with human participants should be the main goal of stem cell research. Therefore, making a strong bridge between preclinical and clinical studies is mandatory for finding the best trail in cell therapy [91].

As well, it is necessary to run more rigorous clinical trials such as RCTs and also animal researches in providing MSC therapy as a safe, effective, and beneficial approach for various diseases. Already, completed human trials displayed only limited outcome. However, applying MSCs in SCIs seems to cause no harm. Different trials [92, 93] indicated the safety of MSC therapy showing no side effects [94]. Regardless of these findings about safety of stem cell therapy, clinical outcomes showed poor results compared to expectations. Among the others, it seems that not many studies particularly encourage cell therapy [95].

Consequently, ongoing trials will almost certainly help and develop comprehension about the outcomes of stem cell therapy [96]. Unfortunately, translation of encouraging data from preclinical studies into clinical administration seems intricate. This probably reflects the multivariable and sophisticated paraplegia physiopathology, requiring a multi-aspect curative approach. To tell the truth, many points require further illuminating and depicting, such as:


#### *Paraplegia*

As a result, prospect preclinical and clinical studies based on MSCs should put emphasis on multivariable factors [98]. For instance, considering donor-related properties like sex, age, and comorbidities that may have an effect on the capacity and excellence of cells is important. Moreover, a better appreciation of the accurate and beneficial methods of action calling for ad hoc investigations will also able to scrutinize MSC complexity, for instance, stem versus stromal. MSC interactions with host tissues have to be considered too. The development of precious in vitro and in vivo models is to be applied in a number of medical conditions; and choosing reagents and techniques that may be administrated from experimental studies to clinical developments for preserving cell consistency and eventually reducing manufacturing expenses is imperative markedly [99].
