Open access peer-reviewed chapter

Mesenchymal Stem Cell Therapies for Paraplegia: Preclinical and Clinical Studies

Written By

Fereshteh Azedi, Kazem Mousavizadeh and Mohammad Taghi Joghataei

Submitted: October 24th, 2019 Reviewed: June 23rd, 2020 Published: May 12th, 2021

DOI: 10.5772/intechopen.93249

From the Edited Volume

Paraplegia

Edited by José Juan Antonio Ibarra Arias and Carlos Alberto Cuellar Ramos

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Abstract

Paraplegia is the damage or loss of function in motor and/or sensory abilities. This insult can be observed in the thoracic, lumbar, or sacral parts of spinal column. Besides, paraplegia may be occurring because of any injuries or diseases of the lower segments or peripheral nerves or by cerebral palsy (CP). This damage can be seen as a result of a tumor or blood clot on the spinal cord. By now, there is not any curative treatment for paraplegia. Using mesenchymal stem cells (MSCs) in the treatment of spinal cord injury is a promising tested strategy because of their simplicity of isolation/preservation and their properties. Several preclinical studies in this field can be found; however, MSCs showed weak and conflicting outcomes in trials. In this chapter book, we will discuss about the therapeutic role of these cells in the treatment of paraplegia, with emphasis on their characterization, relevance, boundaries, and prospect views.

Keywords

  • paraplegia
  • stem cell therapy
  • mesenchymal stem cell
  • preclinical study
  • clinical study

1. Introduction

Paralysis of the lower parts of the body (paraplegia) can be caused by any damage to the spinal cord [1, 2]. Traumatic and nontraumatic injuries are classifications of this disease [3]. Paraplegia causes severe and in most cases lasting changes in the patient’s lifetime and lifestyle [4, 5].

Attempts to find a complete cure for paraplegia and several discoveries show that in adult mammalian, by the preparation of appropriate microenvironment, regeneration of spinal cord axons can be obtained [6]. But then, why can we see the huge delay in the processing of bench to bedside in spite of these findings? Unfortunately, spinal cord scientists find a new barrier in the regeneration field. In fact, axons do regenerate up and down through a graft or transplant placed at the damage site; however, when they reach healthy cord tissue beyond the injury zone, they fail to regenerate more at once [7]. The most important cause for this provision is that the axons of neural networks need to cross through during sufficient stabilized conditions which are unreceptive and intractable to new restoration. Successful elongated distance regeneration is probable only within destabilized neural tissues [8].

Recently, rapid progresses in multipotent stem cell (routinely called mesenchymal stromal/stem cells) investigations increase the interest of scientists to study about the cell therapy and regenerative medicine [9, 10, 11].

Mesenchymal stem cell transplantation in patients suffering paraplegia is considered as a strategy for increasing neuroregeneration [12, 13, 14]. Notably, because of the disproportion in the technique and method of MSC preparation for paraplegia treatment like how they administrate and which criteria are chosen for selecting patients, MSC transplantation is in the initial stages, and there is confusion about the consequences at present [15].

MSCs have various sources in the body including the bone marrow [16, 17], adipose [18], muscle [19], peripheral blood [20], umbilical cord [21, 22, 23], placenta [24], endometrial [25, 26] and menstrual blood [27, 28, 29], fetal tissue [30], and amniotic fluid [31]. Previous finding indicated that these clonal cells can adhere to plastic; express cluster of differentiation (CD) markers like CD73, CD90, and CD105 markers [32]; and can differentiate into adipogenic [33], chondrogenic [34], osteogenic [35, 36], and neurogenic [37, 38, 39] lineages in the experimental condition (in vitro). However, it can be observed many different reports in their strength and self-renewal potential [40]. Accordingly, when we compare previous surveys, variable or even conflicting results can be seen. The lack of uniform methods in MSC characterization, both in preclinical and clinical studies, contributes to this confusion. It is interesting that even the name “MSCs” has still been gradually questioned. Actually, an urgent demand is required to understand the novel sources and potencies of MSCs especially for applying in SCI treatment.

Previous findings showed that the optimistic effect of MSC in treatment of spinal cord and peripheral nerve injury ascribed to their differentiation ability. They can differentiate into various cell lineages and modulate the inflammation process and immunomodulatory responses. [41] MSCs can diminish cell apoptosis and secrete various neurotrophic factors [42, 43].

According to previous studies, transplanting enough cells is important to obtain the best outcome after MSC transplantation and also applying especial techniques for achieving the highest possible survival of MSCs. Likewise, it seems that repeated doses of MSC therapy might be helpful [44].

Findings obtained about clinical trials for SCI treatment demonstrated that the efficacy of MSCs in human studies is not beneficial like in preclinical studies [45]. For these reasons protocol standardization of basic and preclinical studies using MSCs should emphasize to translate to the clinical setting. This chapter book is based on preclinical studies and clinical trials dealing with MSC therapy for paraplegia with emphasis on the challenges in this field.

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2. Paraplegia: mechanisms of degeneration

SCI is included in two mechanisms: primary and secondary damage. When the direct physical injury to the spinal cord happened like any contusion, compression, contraction, and laceration, it can be called primary injury [46]. In this condition, axons separate from each other, mechanical injury to cells occurs directly, and blood vessels rupture. The progress of the injury site can occur in secondary phase, and it can be led to the restorative process [47]. This phase is including alterations in concentration of local ionic, blood pressure dysregulation (local and systemic), decrease of blood flow in the spine, disruption in the blood-brain barrier (BBB), diffusion of proteins from serum into the spinal cord, alterations in inflammatory chemokines and cytokines, cell apoptosis, excitotoxicity, activation of calpain proteases, accumulation of neurotransmitter, production of free radicals, lipid peroxidation, and activation of matrix metalloproteinases (MMPs). All of these changes can lead to demyelination of axons and also ischemia, necrosis, and apoptosis of spinal cord tissue [48]. As a result of these alterations, the inhibitory prospect overcomes, and axonal regrowth constrains. By this reason, injured axons cannot regenerate for a second time [49].

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3. Mesenchymal stem cells: a historical outline

The pathologist Cohnheim in 1867 could show the first evidence of nonhematopoietic stem cells in the bone marrow (BM) and their potency to be the source of fibroblasts involved in wound healing [50]. However, only a century later (50 years ago), the isolation and culture of these cells in an experimental condition successfully could be done. Friedenstein and his colleagues found that, when isolated cells from the rat bone marrow are cultured, a population of fibroblastic-shape nonhematopoietic cells that adhered to the plastic of the cell culture dish could be seen. Then these cells were called as a colony-forming unit fibroblast (CFU-F). These cells were capable of self-maintenance and multi-lineage differentiation like adipocytes, chondrocytes, and osteocytes in vitro and also could support hematopoietic stroma when a single cell was transplanted into animal models [51]. In 1988, Owen showed that a stromal system existed, with a stromal stem cell (CFU-F) at the base of the hierarchy, popularizing the stromal cell terminology [52]. Altogether, this information was generated from in vivo studies.

Only in 1992, Haynesworth and his colleagues enriched and expanded cells in culture with the osteochondrogenic potential of the human bone marrow [53]. In the early 1990s, the proliferation and differentiation potency of these cells in an experimental condition and also multipotency and self-renewal properties after transplantation lead to characteristics of the “stemness” [54]. Thus, the term mesenchymal stem cell (MSC) was proposed by Caplan for progenitor cells, which were isolated from the human adult bone marrow (BM) instead of the term “stromal” or “osteogenic” stem cell and acquired a broad recognition [55]. Figure 1 shows the representation of the most imperative results related to MSC discovery, characterization, and clinical relevance.

Figure 1.

Representation of the most significant findings associated with MSC discovery, description, and clinical purpose.

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4. Preclinical researches using mesenchymal stem cells for paraplegia treatment

Transplantation of MSCs has been well established by several researchers. MSCs have significant effects on the several cellular and molecular cascades. Therefore, they can be regarded as a possible candidate for treating of CNS diseases [56]. MSCs have anti-inflammatory representation [57], immunomodulatory regulation [58, 59], and neuroprotective [60] effects. Moreover, previous findings showed that these cells could secrete trophic factors; thus they could motivate axon regeneration finally leading to functional recovery improvement [61, 62].

Regarding to the paracrine effect, MSCs can produce trophic and neurotropic factors such as insulin-like growth factor (IGF), brain-derived neurotrophic factor (BDNF) [63], vascular endothelial growth factor (VEGF) [64], granulocyte-macrophage colony-stimulating factor (GMCSF), fibroblast growth factor-2 (FGF2) [65], and transforming growth factor beta (TGF-β) [66]. In addition, gene therapy is another field that MSC therapy can be combined with, for example, introducing special genes into MSCs to generate molecules that have great curative ability and can increase neural survival and regeneration [67, 68]. Table 1 presents a summary of preclinical studies by applying MSCs for paraplegia.

Animal Type of lesion Cell source Route of administration Effects on neural regeneration Ref.
Rat Contusion Human mesenchymal precursor cells Lesion site Functional recovery enhancement and tissue sparing and cyst volume decrease [69]
Rat Contusion Human bone marrow MSCs Lesion site, intracisternal, intravenous Improvement in functional recovery [70]
Rat Hemisection Bone marrow MSCs induced in Schwann cells Lesion site Progress in locomotor and sensory scores, axonal regeneration and remyelination [71]
Rat Contusion Bone marrow MSCs Lesion site, intravenous Enhancement in locomotor scores and nerve growth factor (NGF) expression [72]
Rat Transection to the dorsal columns and tracts Bone marrow MSCs, adipose derived-MSCs Lesion site Progress in locomotor scores, increased angiogenesis, preserved axons, reduced numbers of ED1-positive [73]
Rat Hemisection Human umbilical cord-derived MSCs Lesion site Suppression of mechanical allodynia modulation of microglia in the spinal cord [74]
Rat Hemisection Human bone marrow MSCs Lesion site Improvement of locomotor aspect, shorter latency of somatosensory-evoked potentials and different cell types [75]
Rat Hemisection Bone marrow-MSCs Lesion site Enhancement in locomotor aspect and reduction of lesion cavity formation [76]
Rat Contusion Human bone marrow MSCs Lesion site Improvement in functional recovery, tissue sparing and decrease in the volume of lesion cavity and in the white matter loss [77]
Mouse Compression Bone marrow MSCs Lesion site Improvement in locomotor and sensory scores and reduced lesion volume [78]
Mouse Transection Bone marrow MSCs Lesion site Improvement in functional recovery and neuronal survival, reduction of cavity volume and decrease of inflammation, progress in angiogenesis, and reduction of cavity formation [79]
Dog Compression Bone marrow, adipose, Wharton’s jelly, umbilical cord derived MSCs Lesion site Improvement in functional recovery scores, elevated numbers of surviving neurons, lesser lesion sizes and fewer microglia, and reactive astrocytes in the epicenter of the lesion [80]
Dog Compression Neural-induced adipose derived-MSCs Lesion site Improvement in functional recovery and neuronal regeneration and decline of fibrosis [81]
Dog Compression Umbilical cord MSCs Lesion site Improvement in functional recovery, promotion of neuronal regeneration, and diminishing of fibrosis [82]
Dog Compression Human umbilical cord MSCs Lesion site Amelioration in functional recovery and remyelination [83]
Dog Chronic paraplegia (≥6 months) Adipose tissue derived MSCs Lesion site, intraparenchymal Improved locomotion, no adverse effects or complexity, no changes in deep pain perception [84]
Monkey Dorsal SCI Differentiated BM-MSCs into neural lineage cells Lesion site Motor-evoked potential (MEP), somatosensory-evoked potential in cortex (CSEP), and functional recovery and de novo neurogenesis [85]

Table 1.

Summary of preclinical surveys using MSCs for treatment of paraplegia.

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5. Clinical trials using mesenchymal stem cell for paraplegia

The clinical trials conducted for the treatment of paraplegia include three different phases. Phase 1 trials begin with the cell transplantation to a human participant, and the aim of these trials is to study any events such as adverse or toxic effects and also the safety of this intervention. During these trials, subjects may be exposed to some risks and obtain low benefits at the end. In phase 2, the goal of the trial is to determine the potential and variety of an intervention compared to a control group. Typically, the participants are recruited and arbitrarily assigned to the groups as experimental or control, and both participants and investigators are in blind condition, which means they do not have any insight about which of them have been assigned [86]. In phase 3, the conclusive clinical trial and the objective normally affirm the preliminary results obtained at the phase 2, with a significant clinical profit of the therapeutic intervention which has been proved by statistic methods. The number of participants is also larger, and manifold centers are elaborated in the trial [87]. By now, the majority of the studies using MSCs for paraplegia treatment are in phase 1 or 2 (Table 2).

Currently, clinical trials with applying mesenchymal stem cells for treatment of paraplegia are growing, suggesting that despite the existence of numerous questions at primary and preclinical levels, the MSC is considered supposedly valuable for translational researches [46].

Title Lesion type Cell source Phase of the study Effects on neural regeneration ClinicalTrials.gov identifier
Safety study of local administration of autologous bone marrow stromal cells in chronic paraplegia (CME-LEM1) Chronic paraplegia Autologous bone marrow stromal cells Phase I, completed Motor enhancement, alteration in the chronic pain, improvement of neurophysiological parameters, and morphology changes in the spinal cord on neuroimaging follow-up NCT01909154
Autologous mesenchymal stem cells transplantation in thoracolumbar chronic and complete spinal cord injury spinal cord injury Thoracolumbar chronic and complete SCI Autologous bone marrow mesenchymal stem cells Phase II, not yet recruiting Not informed NCT02574585
Autologous mesenchymal stem cells transplantation for spinal cord injury—a phase I clinical study Traumatic spinal cord injury at the thoracic level Autologous BM MSCs Completed Intrathecal administration of BMMSCs is safe with no adverse events NCT02482194
The effect of intrathecal transplantation of autologous adipose tissue derived MSCs in the patients with SCI, phase I clinical study Clinical diagnosis of SCI Autologous adipose-derived MSCs Phase I, completed Mild improvements in neurological function, free of serious adverse events NCT01624779
Phase I, single center, trial to assess safety and tolerability of the intrathecal infusion of ex-vivo expanded bone-marrow derived MSCs for the treatment of SCI SCI clinical diagnosis (ASIA A) Autologous bone marrow MSCs Active, not recruiting Not informed NCT01162915
Study the safety and efficacy of bone marrow derived autologous cells for the treatment of SCI SCI clinical diagnosis Autologous bone marrow MSCs Recruiting Not informed NCT01730183
Phase I study of autologous bone marrow stem cell transplantation in patients with spinal cord injury Traumatic thoracic or lumbar SCI Autologous bone marrow MSCs Phase I Transplantation of autologous BMSCs is a feasible and safe technique NCT01325103
Surgical transplantation of autologous bone marrow stem cells with glial scar resection for patients of chronic SCI and intra-thecal injection for acute and subacute injury—a preliminary study Complete transection of spinal cord Autologous bone marrow MSCs Completed Not informed NCT01186679
Autologous adipose derived MSCs transplantation in patient with spinal cord injury Clinical diagnosis of spinal cord injury Autologous AD MSCs Phase I, completed Intravenous administration of AD-MSCs is safe with no adverse events NCT01274975
Difference between rehabilitation therapy and stem cells transplantation in patients with spinal cord injury in China Traumatic injury, spinal cord injury U-MSCs Phase II, completed Patients receiving U-MSCs demonstrate improved urinary control, muscle tension, motion, and self-care ability NCT01393977

Table 2.

Summary of trials using mesenchymal stem cell for treatment of paraplegia.

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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:

  1. The best therapeutic protocols with respect to the preparation method, type, and amount of stem cells transplanted.

  2. The paracrine effects and their impact on behavioral and functional improvement.

  3. The rout of stem cell delivery and timing of transplantation.

  4. The substance of cellular matrix and microenvironment.

  5. The ability of neuroplasticity and production of new connections from injured neuronal cells.

  6. The ethical aspects and financial challenges associated with stem cell research [97].

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].

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7. Conclusion

Nowadays, the advancements in cell marketing with the progress in cell isolation, description, and quality control will positively encourage scientists to apply MSCs for treating several diseases and disorders, even with all remaining challenges.

Preclinical studies revealed the importance of MSC therapy in the SCI and paraplegia field. Unluckily, the effect of MSC therapy is not typically seen in the human studies, and the results need a long time from being similar to preclinical studies. Consequently, among other concerns, the protocol standardization in source of cells, culture conditions, time of cell delivery after paraplegia, number and administration rout of cells, plasticity, and potential of MSCs after isolation and expansion in vitro is of urgency. Confidently, preliminary studies with emphasis on these key points will be helpful in terms of their winning implementation of human studies.

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Conflict of interest

The authors declare no conflict of interest.

References

  1. 1. Besalti O, Aktas Z, Can P, Akpinar E, Elcin AE, Elcin YM. The use of autologous neurogenically-induced bone marrow-derived mesenchymal stem cells for the treatment of paraplegic dogs without nociception due to spinal trauma. The Journal of Veterinary Medical Science. 2016;78(9):1465-1473
  2. 2. McDonald JW, Sadowsky C. Spinal-cord injury. Lancet. 2002;359(9304):417-425
  3. 3. Dubey A, Tomar S, Gupta A, Khandelwal D. Delayed paraplegia in an adult patient with spinal cord injury without radiographic abnormality of dorsal spine: A lesson learned. Asian Journal of Neurosurgery. 2018;13(3):867-869
  4. 4. Ke X, Wang Y, Zhang A, Jiang Y, Dong C, Wang Q , et al. Neurological protection effects of “paraplegia-triple-needling method” on rats with incomplete spinal cord injury. Zhongguo Zhen Jiu. 2015;35(6):585-589
  5. 5. Courtine G, van den Brand R, Musienko P. Spinal cord injury: Time to move. Lancet. 2011;377(9781):1896-1898
  6. 6. Fitch MT, Silver J. CNS injury, glial scars, and inflammation: Inhibitory extracellular matrices and regeneration failure. Experimental Neurology. 2008;209(2):294-301
  7. 7. Nash M, Pribiag H, Fournier AE, Jacobson C. Central nervous system regeneration inhibitors and their intracellular substrates. Molecular Neurobiology. 2009;40(3):224-235
  8. 8. Busch S, Silver J. The role of extracellular matrix in CNS regeneration. Current Opinion in Neurobiology. 2007;17:120-127
  9. 9. Oh SK, Jeon SR. Current concept of stem cell therapy for spinal cord injury: A review. Korean Journal of Neurotrauma. 2016;12(2):40-46
  10. 10. Jeong SK, Choi I, Jeon SR. Current status and future strategies to treat spinal cord injury with adult stem cells. Journal of Korean Neurosurgical Association. 2020;63(2):153-162
  11. 11. Yong KW, Choi JR, Dolbashid AS, Wan Safwani WKZ. Biosafety and bioefficacy assessment of human mesenchymal stem cells: What do we know so far? Regenerative Medicine. 2018;13(2):219-232
  12. 12. Zhang D, He X. A meta-analysis of the motion function through the therapy of spinal cord injury with intravenous transplantation of bone marrow mesenchymal stem cells in rats. PLoS One. 2014;9(4):e93487
  13. 13. Alessandrini M, Preynat-Seauve O, De Bruin K, Pepper MS. Stem cell therapy for neurological disorders. South African Medical Journal. 2019 10;109(8b):70-77
  14. 14. Mukhamedshina Y, Shulman I, Ogurcov S, Kostennikov A, Zakirova E, Akhmetzyanova E, et al. Mesenchymal stem cell therapy for spinal cord contusion: A comparative study on small and large animal models. Biomolecules. 2019;9(12):811
  15. 15. Goel A. Stem cell therapy in spinal cord injury: Hollow promise or promising science? Journal of Craniovertebral Junction and Spine. 2016;7(2):121-126
  16. 16. Vaquero J, Zurita M. Bone marrow stromal cells for spinal cord repair: A challenge for contemporary neurobiology. Histology and Histopathology. 2009;24(1):107-116
  17. 17. An H, Li Q , Wen J. Bone marrow mesenchymal stem cells encapsulated thermal-responsive hydrogel network bridges combined photo-plasmonic nanoparticulate system for the treatment of urinary bladder dysfunction after spinal cord injury. Journal of Photochemistry and Photobiology. B. 2020;203:111741
  18. 18. Radtke C, Schmitz B, Spies M, Kocsis J, Vogt P. Peripheral glial cell differentiation from neurospheres derived from adipose mesenchymal stem cells. International Journal of Developmental Neuroscience. 2009;27:817-823
  19. 19. Latil M, Rocheteau P, Châtre L, Sanulli S, Mémet S, Ricchetti M, et al. Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity. Nature Communications. 2012;3:903. DOI: 101038/ncomms1890
  20. 20. Dunac A, Frelin C, Popolo-Blondeau M, Chatel M, Mahagne M, Philip P. Neurological and functional recovery in human stroke are associated with peripheral blood CD34+ cell mobilization. Journal of Neurology. 2007;254:327-332
  21. 21. Shahbazi A, Safa M, Alikarami F, Kargozar S, Asadi MH, Joghataei MT, et al. Rapid induction of neural differentiation in human umbilical cord matrix mesenchymal stem cells by cAMP-elevating agents. International Journal of Molecular and Cellular Medicine. 2016;5(3):167-177
  22. 22. Tian DZ, Deng D, Qiang JL, Zhu Q , Li QC, Yi ZG. Repair of spinal cord injury in rats by umbilical cord mesenchymal stem cells through P38MAPK signaling pathway. European Review for Medical and Pharmacological Sciences. 2019;23(3 Suppl):47-53
  23. 23. Bagher Z, Azami M, Ebrahimi-Barough S, Mirzadeh H, Solouk A, Soleimani M, et al. Differentiation of Wharton’s jelly-derived mesenchymal stem cells into motor neuron-like cells on three-dimensional collagen-grafted nanofibers. Molecular Neurobiology. 2015;53(4):2397-2408
  24. 24. Long C, Lankford L, Kumar P, Grahn R, Borjesson DL, Farmer D, et al. Isolation and characterization of canine placenta-derived mesenchymal stromal cells for the treatment of neurological disorders in dogs. Cytometry. Part A. 2017;93(1):82-92
  25. 25. Sahoo AK, Das JK, Nayak S. Isolation, culture, characterization, and osteogenic differentiation of canine endometrial mesenchymal stem cell. Veterinary World. 2018;10(12):1533-1541
  26. 26. Gargett CE, Masuda H. Adult stem cells in the endometrium. Molecular Human Reproduction. 2010;16(11):818-834
  27. 27. Azedi F,Kazemnejad S, Zarnani A, Behzadi G, Vasei M, Khanmohammadi M, et al. Differentiation potential of menstrual blood- versus bone marrow stem cells into glial-like cells. Cell Biology International. 2014;38(2014):615-624
  28. 28. Azedi F, Kazemnejad S, Zarnani A, Soleimani M, Shojaei A, Arasteh S. Comparative capability of menstrual blood versus bone marrow derived stem cells in neural differentiation. Molecular Biology Reports. 2017;44(1):169-182
  29. 29. Allickson JG, Sanchez A, Yefimenko N, Borlongan CV, Sanberg PR. Recent studies assessing the proliferative capability of a novel adult stem cell identified in menstrual blood. Open Stem Cell Journal. 2011;3(2011):4-10
  30. 30. Bachoud-Levi A, Gaura V, Brugieres P, et al. Effect of fetal neural transplants in patients with Huntington’s disease 6 years after surgery: A long-term follow-up study. Lancet Neurology. 2006;5:303-309
  31. 31. Harrell CR, Gazdic M, Fellabaum C, Jovicic N, Djonov V, Arsenijevic N, et al. Therapeutic potential of amniotic fluid derived mesenchymal stem cells based on their differentiation capacity and immunomodulatory properties. Current Stem Cell Research & Therapy. 2019;14(4):327-336
  32. 32. Ding DC, Shyu WC, Lin SZ. Mesenchymal stem cells. Cell Transplantation. 2011;20(1):5-14
  33. 33. Baer PC, Koch B, Hickmann E, Schubert R, Cinatl J Jr, Hauser IA, et al. Isolation, characterization, differentiation and immunomodulatory capacity of mesenchymal stromal/stem cells from human perirenal adipose tissue. Cell. 2019;8(11):0. DOI: 10.3390/cells8111346
  34. 34. Khanmohammadi M, Khanjani S, Bakhtyari MS, Zarnani AH, Edalatkhah H, Akhondi MM, et al. Proliferation and chondrogenic differentiation potential of menstrual blood- and bone marrow-derived stem cells in two-dimensional culture. International Journal of Hematology. 2012;95(5):484-493
  35. 35. Atmani H, Chappard D, Basle M. Proliferation and differentiation of osteoblasts and adipocytes in rat bone marrow stromal cell cultures: Effects of dexamethasone and calcitriol. Journal of Cellular Biochemistry. 2003;2:364-372
  36. 36. Darzi S, Zarnani AH, Jeddi-Tehrani M, Entezami K, Mirzadegan E, Akhondi MM, et al. Osteogenic differentiation of stem cells derived from menstrual blood versus bone marrow in the presence of human platelet releasate. Tissue Engineering. Part A. 2012;18(15-16):1720-1728
  37. 37. Hernandez R, Jimenez-Luna C, Perales-Adan J, Perazzoli G, Melguizo C, Prados J. Differentiation of human mesenchymal stem cells towards neuronal lineage: Clinical trials in nervous system disorders. Biomolecules & Therapeutics (Seoul). 2019;28(1):34-44
  38. 38. Zemelko V, Kozhukharova I, Alekseenko L, Reshetnikova G, Puzanov M, Grinchuk T, et al. Neurogenic potential of human mesenchymal stem cells isolated from bone marrow, adipose tissue and endometrium: A comparative study. Cell and Tissue Biology. 2013;7(3):235-244
  39. 39. Woodbury D, Schwarz EJ, Prockop DJ, Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons. Journal of Neuroscience Research. 2000;61:364-370
  40. 40. Bhat IA, Sivanarayanan TB, Somal A, Pandey S, Bharti MK, Panda BSK, et al. An allogenic therapeutic strategy for canine spinal cord injury using mesenchymal stem cells. Journal of Cellular Physiology;234(3):2705-2718
  41. 41. Chaudhary D, Trivedi RN, Kathuria A, Goswami TK, Khandia R, Munjal A. In vitro and in vivo Immunomodulating properties of mesenchymal stem cells. Recent Patents on Inflammation & Allergy Drug Discovery. 2018;12(1):59-68
  42. 42. Leyendecker A Jr, Pinheiro CCG, Amano MT, Bueno DF. The use of human mesenchymal stem cells as therapeutic agents for the in vivo treatment of immune-related diseases: A systematic review. Frontiers in Immunology. 2018;9:2056
  43. 43. Liu X, Xu W, Zhang Z, Liu H, Lv L, Han D, et al. VEGF-transfected BMSC improve the recovery of motor and sensory functions of rats with spinal cord injury. Spine (Phila Pa 1976). 2020;45(7):E364-E372
  44. 44. Gong Z, Xia K, Xu A, Yu C, Wang C, Zhu J, et al. Stem cell transplantation: A promising therapy for spinal cord injury. Current Stem Cell Research & Therapy. 2020;15(4):321-331
  45. 45. Huang H, Chen L, Sanberg P. Cell therapy from bench to bedside translation in CNS neurorestoratology era. Cell Medicine. 2010;1(1):15-46
  46. 46. Blanco Martinez AM, Goulart C, Ramalho BS, Oliveira J, Almeida F. Neurotrauma and mesenchymal stem cells treatment: From experimental studies to clinical trials. World Journal of Stem Cells. 2014;6(2):179-194
  47. 47. Granger N, Carwardine D. Acute spinal cord injury: Tetraplegia and paraplegia in small animals. The Veterinary Clinics of North America. Small Animal Practice. 2014;44(6):1131-1156
  48. 48. Dumont R, Okonkwo D, Verma S, Hurlbert R, Boulos P, Ellegala D, et al. Acute spinal cord injury, part I: Pathophysiologic mechanisms. Clinical Neuropharmacology. 2001;24:254-264
  49. 49. McKerracher L, David S, Jackson D, Kottis V, Dunn R, Braun P. Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth. Neuron. 1994;13:805-811
  50. 50. Chamberlain G, Fox J, Ashton B, Middleton J. Concise review: Mesenchymal stem cells: Their phenotype, differentiation capacity, immunological features, and potential for homing. Stem Cells. 2007;25(11):2739-2749
  51. 51. Friedenstein A, Chailakhjan R, Lalykina K. The development of fibroblast colonies in monolayer cultures of Guinea-pig bone marrow and spleen cells. Cell and Tissue Kinetics. 1970;3(4):393-403
  52. 52. Meirelles L, Fontes A, Covas D, Caplan A. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine & Growth Factor Reviews. 2009;20(5):419-427
  53. 53. Haynesworth S, Goshima J, Goldberg V, Caplan A. Characterization of cells with osteogenic potential from human marrow. Bone. 1992;13(1):81-88
  54. 54. Nombela-Arrieta C, Ritz J, Silberstein L. The elusive nature and function of mesenchymal stem cells. Nature Reviews. Molecular Cell Biology. 2011;12(2):126-131
  55. 55. Torre M, Lucarelli E, Guidi S. Ex vivo expanded mesenchymal stromal cell minimal quality requirements for clinical application. Stem Cells and Development. 2015;24(6):677-685
  56. 56. Matthay M, Pati S, Lee J. Concise review: Mesenchymal stem (stromal) cells: Biology and preclinical evidence for therapeutic potential for organ dysfunction following trauma or sepsis. Stem Cells. 2017;35:316-324
  57. 57. Najar M, Krayem M, Merimi M, Burny A, Meuleman N, Bron D, et al. Insights into inflammatory priming of mesenchymal stromal cells: Functional biological impacts. Inflammation Research. 2018;67(6):467-477
  58. 58. Bai L, Lennon D, Eaton V, Maier K, Caplan A, Miller S, et al. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia. 2009;57:1192-1203
  59. 59. Salami F, Tavassoli A, Mehrzad J, Parham A. Immunomodulatory effects of mesenchymal stem cells on leukocytes with emphasis on neutrophils. Immunobiology;223(12):786-791
  60. 60. Chen X, Wu J, Sun R, Zhao Y, Li Y, Pan J, et al. Tubular scaffold with microchannels and an H-shaped lumen loaded with BMSCs promotes neuroregeneration and inhibits apoptosis after spinal cord injury. Journal of Tissue Engineering and Regenerative Medicine. 2020;14(3):397-411
  61. 61. Chudickova M, Vackova I, Machova Urdzikova L, Jancova P, Kekulova K, Rehorova M, et al. The effect of Wharton jelly-derived mesenchymal stromal cells and their conditioned media in the treatment of a rat spinal cord injury. International Journal of Molecular Sciences. 2019;20(18):4516
  62. 62. Li C, Jiao G, Wu W, Wang H, Ren S, Zhang L, et al. Exosomes from bone marrow mesenchymal stem cells inhibit neuronal apoptosis and promote motor function recovery via the Wnt/beta-catenin signaling pathway. Cell Transplantation. 2019;28(11):1373-1383
  63. 63. Zhang T, Liu C, Chi L. Suppression of miR-10a-5p in bone marrow mesenchymal stem cells enhances the therapeutic effect on spinal cord injury via BDNF. Neuroscience Letters. 2019;714:134562
  64. 64. Xu ZX, Zhang LQ , Zhou YN, Chen XM, Xu WH. Histological and functional outcomes in a rat model of hemisected spinal cord with sustained VEGF/NT-3 release from tissue-engineered grafts. Artificial Cells, Nanomedicine and Biotechnology. 2020;48(1):362-376
  65. 65. Huang XR, Xu H, Zhang Y, Jiang YB, Xia CL, Fang SC. Repair effect of bFGF combined with bone marrow mesenchymal stem cells on spinal cord injury in rats. Zhongguo Gu Shang. 2019;32(7):653-657
  66. 66. Sohrabi Akhkand S, Amirizadeh N, Nikougoftar M, Alizadeh J, Zaker F, Sarveazad A, et al. Evaluation of umbilical cord blood CD34+ hematopoietic stem cells expansion with inhibition of TGF-beta receptorII in co-culture with bone marrow mesenchymal stromal cells. Tissue & Cell. 2016;48(4):305-311
  67. 67. Huang JH, Xu Y, Yin XM, Lin FY. Exosomes derived from miR-126-modified MSCs promote angiogenesis and neurogenesis and attenuate apoptosis after spinal cord injury in rats. Neuroscience. 2019;424:133-145
  68. 68. Wang X, Ye L, Zhang K, Gao L, Xiao J, Zhang Y. Upregulation of microRNA-200a in bone marrow mesenchymal stem cells enhances the repair of spinal cord injury in rats by reducing oxidative stress and regulating Keap1/Nrf2 pathway. Artificial Organs. 2020;44(7):744-752
  69. 69. Hodgetts S, Simmons P, Plant G. A comparison of the behavioral and anatomical outcomes in sub-acute and chronic spinal cord injury models following treatment with human mesenchymal precursor cell transplantation and recombinant decorin. Experimental Neurology. 2013;248:343-359
  70. 70. Shin D, Kim J, Kim H, Yi S, Ha Y, Yoon DH, et al. Comparison of functional and histological outcomes after intralesional, intracisternal, and intravenous transplantation of human bone marrow-derived mesenchymal stromal cells in a rat model of spinal cord injury. Acta Neurochirurgica. 2013;155:1943-1950
  71. 71. Zaminy A, Shokrgozar M, Sadeghi Y, Noroozian M, Heidari M, Piryaei A. Mesenchymal stem cells as an alternative for Schwann cells in rat spinal cord injury. Iranian Biomedical Journal. 2013;17:113-122
  72. 72. Kang E, Ha K, Kim Y. Fate of transplanted bone marrow derived mesenchymal stem cells following spinal cord injury in rats by transplantation routes. Journal of Korean Medical Science. 2012;27:586-593
  73. 73. Zhou Z, Chen Y, Zhang H, Min S, Yu B, He B, et al. Comparison of mesenchymal stromal cells from human bone marrow and adipose tissue for the treatment of spinal cord injury. Cytotherapy. 2013;15:434-448
  74. 74. Roh D, Seo M, Choi H, Park S, Han H, Beitz A, et al. Transplantation of human umbilical cord blood or amniotic epithelial stem cells alleviates mechanical allodynia after spinal cord injury in rats. Cell Transplantation. 2013;22:1577-1590
  75. 75. Choi J, Leem J, Lee K, Kim S, Suh-Kim H, Jung S, et al. Effects of human mesenchymal stem cell transplantation combined with polymer on functional recovery following spinal cord hemisection in rats. The Korean Journal of Physiology & Pharmacology. 2012;16:405-411
  76. 76. Wei X, Wen Y, Zhang T, Li H. Effects of bone marrow mesenchymal stem cells with acellular muscle bioscaffolds on repair of acute hemi-transection spinal cord injury in rats. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2012;26:1362-1368
  77. 77. Alexanian A, Fehlings M, Zhang Z, Maiman D. Transplanted neurally modified bone marrow-derived mesenchymal stem cells promote tissue protection and locomotor recovery in spinal cord injured rats. Neurorehabilitation and Neural Repair. 2011;25:873-880
  78. 78. Boido M, Garbossa D, Fontanella M, Ducati A, Vercelli A. Mesenchymal stem cell transplantation reduces glial cyst and improves functional outcome after spinal cord compression. World Neurosurgery. 2014;81:183-190
  79. 79. Zhang W, Yan Q , Zeng Y, Zhang X, Xiong Y, Wang J, et al. Implantation of adult bone marrow-derived mesenchymal stem cells transfected with the neurotrophin-3 gene and pretreated with retinoic acid in completely transected spinal cord. Brain Research. 2010;1359:256-271
  80. 80. Ryu H, Lim J, Byeon Y, Park J, Seo M, Lee Y, et al. Functional recovery and neural differentiation after transplantation of allogenic adiposederived stem cells in a canine model of acute spinal cord injury. Journal of Veterinary Science. 2009;10:273-284
  81. 81. Gu W, Zhang F, Xue Q , Ma Z, Lu P, Yu B. Transplantation of bone marrow mesenchymal stem cells reduces lesion volume and induces axonal regrowth of injured spinal cord. Neuropathology. 2010;30:205-217
  82. 82. Park S, Byeon Y, Ryu H, Kang B, Kim Y, Kim W, et al. Comparison of canine umbilical cord blood-derived mesenchymal stem cell transplantation times: Involvement of astrogliosis, inflammation, intracellular actin cytoskeleton pathways, and neurotrophin-3. Cell Transplantation. 2011;20:1867-1880
  83. 83. Lee J, Chung W, Kang E, Chung D, Choi C, Chang H, et al. Schwann cell-like remyelination following transplantation of human umbilical cord blood (hUCB)-derived mesenchymal stem cells in dogs with acute spinal cord injury. Journal of the Neurological Sciences. 2011;300:86-96
  84. 84. Escalhão C, Ramos I, Hochman-Mendez C. Safety of allogeneic canine adipose tissue-derived mesenchymal stem cell intraspinal transplantation in dogs with chronic spinal cord injury. Stem Cells International. 2017;2017:3053759
  85. 85. Deng Y, Liu X, Liu Z, Liu X, Liu Y, Zhou G. Implantation of BM mesenchymal stem cells into injured spinal cord elicits de novo neurogenesis and functional recovery. Cytotherapy. 2006;8:210-214
  86. 86. Steeves J, Lammertse D, Curt A, Fawcett J, Tuszynski M, Ditunno J, et al. Guidelines for the conduct of clinical trials for spinal cord injury (SCI) as developed by the ICCP panel: Clinical trial outcome measures. Spinal Cord. 2007;45:206-202
  87. 87. Lammertse D, Tuszynski M, Steeves J, Curt A, Fawcett J, Rask C, et al. Guidelines for the conduct of clinical trials for spinal cord injury as developed by the ICCP panel: Clinical trial design. Spinal Cord. 2007;45:232-242
  88. 88. Mastrolia I, Foppiani E, Murgia A, Candini O, Samarelli A, Grisendi G, et al. Challenges in clinical development of mesenchymal stromal/stem cells: Concise review. Stem Cells Translational Medicine. 2019;8:1135-1148
  89. 89. Wyatt L, Keirstead H. Stem cell-based treatments for spinal cord injury. Progress in Brain Research. 2012;201:233-252
  90. 90. Cho S, Kim Y, Kang H, Yim S, Park C, Min YH, et al. Functional recovery after the transplantation of neurally differentiated mesenchymal stem cells derived from bone marrow in a rat model of spinal cord injury. Cell Transplantation. 2016;25(7):1423
  91. 91. Kabat M, Bobkov I, Kumar S, Grumet M. Trends in mesenchymal stem cell clinical trials 2004-2018: Is efficacy optimal in a narrow dose range? Stem Cells Translational Medicine. 2020;9:17-27
  92. 92. Lalu M, McIntyre L, Pugliese C. Safety of cell therapy with mesenchymal stromal cells (SafeCell): A systematic review and meta-analysis of clinical trials. PLoS One. 2012:e47559
  93. 93. Tsuji W, Schnider J, McLaughlin M. Effects of immunosuppressive drugs on viability and susceptibility of adipose- and bone marrow-derived mesenchymal stem cells. Frontiers in Immunology. 2015;6:131
  94. 94. Ra J, Shin I, Kim S, Kang S, Kang B, Lee H. Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells and Development. 2011;20:1297-1308
  95. 95. Jin M, Medress Z, Azad T, Doulames V, Veeravagu A. Stem cell therapies for acute spinal cord injury in humans: A review. Neurosurgical Focus. 2019;46(3):E10
  96. 96. Osaka M, Honmou O, Murakami T. Intravenous administration of mesenchymal stem cells derived from bone marrow after contusive spinal cord injury improves functional outcome. Brain Research. 2010;1343:226-235
  97. 97. Jossen V, van den Bos C, Eibl R. Manufacturing human mesenchymal stem cells at clinical scale: Process and regulatory challenges. Applied Microbiology and Biotechnology. 2018;102:3981-3994
  98. 98. Reger R, Prockop D. Should publications on mesenchymal stem/progenitor cells include in-process data on the preparation of the cells? Stem Cells Translational Medicine. 2014;3:632-635
  99. 99. Martin I, Galipeau J, Kessler C. Challenges for mesenchymal stromal cell therapies. Science Translational Medicine. 2019;11:1-3

Written By

Fereshteh Azedi, Kazem Mousavizadeh and Mohammad Taghi Joghataei

Submitted: October 24th, 2019 Reviewed: June 23rd, 2020 Published: May 12th, 2021