Human umbilical cord derived mesenchymal stem cells in peripheral nerve regeneration
Peripheral nerve injury can occur as a result of trauma or disease and carries significant morbidity including sensory and motor loss. The body has limited ability for nerve regeneration and functional recovery. Left untreated, nerve lesions can cause lifelong disability. Traditional treatment options such as neurorrhaphy and neurolysis have high failure rates. Surgical reconstruction with autograft carries donor site morbidity and often provide suboptimal results. Mesenchymal stem cells (MSCs) are known to have promising regenerative potential and have gained attention as a treatment option for nerve lesions. It is however, unclear whether it can be effectively used for nerve regeneration.
To evaluate the evidence for the use of human umbilical cord derived MSCs (UCMSCs) in peripheral nerve regeneration.
We carried out a systematic literature review in accordance with the PRISMA protocol. A literature search was performed from conception to September 2019 using PubMed, EMBASE and Web of Science. The results of eligible studies were appraised. A risk of bias analysis was carried out using Cochrane’s RoB 2.0 tool.
Fourteen studies were included in this review. A total of 279 subjects, including both human and animal were treated with UCMSCs. Four studies obtained UCMSCs from a third-party source and the remainder were harvested by the investigators. Out of the 14 studies, thirteen conducted xenogenic transplantation into nerve injury models. All studies reported significant improvement in nerve regeneration in the UCMSC treated groups compared with the various different controls and untreated groups.
The evidence summarised in this PRISMA systematic review of in vivo studies supports the notion that human UCMSC transplantation is an effective treatment option for peripheral nerve injury.
Core tip: While human umbilical cord derived mesenchymal stem cells hold promise as a treatment option for peripheral nerve lesions, robust in vivo models are required in order to determine the best method of delivering mesenchymal stem cells to sites of injury.
Peripheral nerve injuries can occur as a result of trauma or disease and can lead to significant morbidity including sensory loss, motor loss and chronic pain. These injuries cause life-long disability in up to 2.8% of all trauma patients. Damage to peripheral nerves most commonly occurs as a result of laceration, compression, ischaemia or traction. As classified by Seddon in 1943, nerve injury can range from focal demyelination termed neurapraxia, to total nerve transection termed neurotmesis[3,4]. The mechanism of recovery post-injury occurs by either branching of collateral axons or by regeneration of the damaged neuron[4,5]. In order for full neuronal recovery to occur, Wallerian degeneration, axonal regeneration and end-organ reinnervation must take place. This is driven by an array of neurotropic factors. However, recovery in function following peripheral nerve injury is hindered by complex pathological mechanisms such as poor nerve regeneration, neuromuscular atrophy, and end-plate degeneration which can lead to suboptimal neuron function[6-9].
Traditionally, peripheral nerve injury can be managed conservatively or surgically with neurolysis, neural suturing, end-to-side neurorrhaphy and nerve autograft[10-12]. Even with optimum surgical repair, most methods will attain partial but not full return of nerve function. Certain peripheral nerve injuries, such as severe brachial plexus or long traction injuries remain inoperable. Autografts have several disadvantages, including donor site morbidity, mismatch in nerve and graft size resulting in poor engraftment, and the potential for development of painful neuromas[11,13,14]. Alternative methods of treating peripheral nerve injuries may be through cell-based regenerative therapies.
Transplantation of mesenchymal stem cells (MSCs), given their regenerative properties and highly proliferative capacity, has been proposed as a promising therapeutic option for peripheral nerve regeneration[16,17]. MSCs are plastic-adherent, undifferentiated, multipotent cells that can be harvested from numerous sites of the body including bone marrow, adipose tissue, dental pulp, amniotic fluid and umbilical cord[17-19]. MSCs from different tissue origins can have distinct cytokine expression profiles, and thus may enable different MSCs to be particularly suited to certain clinical applications[20,21]. Owing to low immunogenicity, MSCs may be transplanted allogenically with minimal consequence. The particular mechanisms through which MSCs aid nerve repair have not yet been fully characterised. MSCs from various sources such as adipose tissue and bone marrow are able to differentiate into Schwann cells[23,24]. While some in vitro experiments suggest that transplanted MSCs may be stimulated by peripheral nerves to differentiate into Schwann cells, alternative findings have instead shown that transplanted MSCs encourage endogenous cells to express regenerative phenotypes. Increasingly, MCSs are believed to mediate their regenerative properties predominantly through paracrine effects[27,28]. Aside from acting through soluble factors, MSCs have also demonstrated the ability to secrete extracellular vesicles that contain bioactive components such as miRNA and cytokines. Indeed, native Schwann cells have been shown to facilitate axonal regeneration following injury through secretion of exosomes that decrease GTPase RhoA activity. Similarly, human MSCs may act to achieve the same result through exosomes by upregulation of the PI3 kinase and Akt signalling cascades.
MSCs from umbilical cord are convenient to harvest from post-natal tissue in a non-invasive manner and possess a high capacity to expand ex vivo. They express low levels of HLA-DR compared to MSCs from other cell sources and therefore pose low risk of immunogenic complications following allogenic transplantation. Through sequential treatment with β-mercaptoethanol and various cytokines, umbilical cord derived MSCs (UCMSCs) can adopt a Schwann-like phenotype. In addition, UCMSCs have been shown to possess greater paracrine effects than those of bone marrow-derived MSCs (BMMSC) and adipose-derived MSCs[17,29], and are able to potentiate axonal regeneration and peripheral nerve functional regeneration through these effects[11,17,29,36]. UCMSCs have been proposed to exert neuroprotective effects through secretion of Brain Derived Neurotrophic Factor (BDNF), angiopoietin-2 and CXCL-16[38,39]. Other studies have suggested that they indirectly promote neurogenesis[40,41]. UCMSCs are also able to indirectly enhance expression of neurotransmitters such as BDNF and neurotrophin-3 (NTF3) which are postulated to aid neuro-regeneration[42,43].
To date, there have been over 400 clinical trials that explore the use of MSCs in transplantation; UCMSCs follow BMMSCs as the second most commonly used cell source. In this PRISMA systematic review, we analyse the evidence for the use of human UCMSCs in peripheral nerve regeneration by examining in vivo studies.
MATERIALS AND METHODS
A literature search was performed from conception to September 2019 using PubMed, EMBASE and Web of Science. The following search terms were used: ((((((((Mesenchymal stem cells) OR mesenchymal stem cell) OR MSC) OR MSCs) OR Mesenchymal stromal cell) OR Mesenchymal cell)) AND (((((Nerve) OR Peripheral nerve) OR Peripheral nerve injury) OR damaged nerve) OR nerve injury)) AND ((((((repair) OR regeneration) OR regrowth) OR regenerate) OR renew) OR restore). We adhered to the recommendations as stipulated by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
We included case series, case control, cohort studies and randomised controlled trials. We enrolled studies that examined peripheral nerve lesions treated with human UCMSCs in in vivo human and animal subjects. Studies that only conducted in vitro experiments were excluded. Studies that investigated central nervous system regeneration using UCMSCs were excluded. All included studies were published in the English language. We excluded all unpublished and retracted literature.
CB and KT carried out the search independently. RoB2 tool was used by CM and BZ to assess the risk of bias in the studies, all discrepancy in results were resolved by discussion.
A total of 210 studies were screened for title, abstract and the inclusion/exclusion criteria were applied (Figure (Figure1).1). One retracted study was excluded. Fourteen studies were reviewed in full text. The overall bias of studies is shown in Figure Figure2.2. The summary of results is shown in Figure Figure3.3. All 14 studies were of a case control design (Table (Table1).1). Four studies obtained UCMSCs from a third-party source and the remainder were harvested directly from human subjects. Out of the 14 studies, ten involved xenogenic transplantation into sciatic nerve injury specimens that were either crushed or transected. The studies were grouped according to Seddon’s seminal nerve injury classification system, which includes axonotmesis (injury to nerve sheath alone) and neurotmesis (injury to the entire nerve). A total of 279 subjects were treated with UCMSCs. All studies reported significant improvement in UCMSC treated groups compared with the various different controls and untreated groups. The studies did not report any significant complications.