Significance
Preterm white matter injury may lead to diverse neurobehavioral defects, and has complex etiology, clinical course, and outcomes. While current treatments for preterm white matter injury are mainly supportive, umbilical cord blood cells exhibit the potential to reduce brain injury. In this review, we focus on the pathogenesis and pathophysiology of preterm white matter injury, and explore the potential effects and treatment options using umbilical cord blood.
1 INTRODUCTION
Of every 10 live births worldwide, one infant is born preterm (<37 weeks gestation) (Blencowe et al., 2012). Moreover, this incidence seems to be increasing (Chawanpaiboon et al., 2019) due to impressive advancements in perinatal and neonatal care (Stoll et al., 2015). Preterm infants carry a high risk of brain injury, which can affect motor, cognitive, social, and sensory functions (Larroque et al., 2008; Lin et al., 2020; Moore et al., 2012). Infants born prematurely may exhibit short-term or long-term neurodevelopmental deficits, which impose heavy burdens on the family and society (Amankwah et al., 2020; Khan et al., 2015; Tonmukayakul et al., 2018).
Over 42.5% of preterm or extremely preterm infants exhibit preterm white matter injury (PWMI), which can lead to long-term neurological deficits (Bax et al., 2006). Historically, periventricular leukomalacia (PVL) was the encephalopathy most frequently described in relation to prematurity (Volpe, 2009), which was later recognized as cystic white matter injury (WMI) (Back, 2017). However, improvements in perinatal and neonatal care have reduced PVL to a rare occurrence with an incidence of <1% in some centers (Groenendaal et al., 2010; van Tilborg et al., 2018). More recently, diffuse WMI has been identified as a major neuropathologic brain injury in premature infants (Back, 2017; Gano et al., 2015; Volpe, 2009).
Neonatal brain injury has been treated via hypothermia (Cotten et al., 2014; Shankaran et al., 2005), and erythropoietin (EPO) therapy may also be useful (Juul & Pet, 2015; Ohls et al., 2014). However, these methods may be unsuitable or have questionable effects in preterm infants with brain injury. Recently, there has been much interest in stem cells or stem-like cells based on their possible effects on tissue repair and/or regeneration. In a meta-analysis, compared with symptomatic standard care only, stem cells treatment for cerebral palsy (CP) improved gross motor function (Eggenberger et al., 2019). The cell types may include embryonic stem cells (ESCs) (Cyranoski, 2018), neural stem cells (NSCs) (Kalladka et al., 2016), induced pluripotent stem cells (iPSCs) (Shi et al., 2017), and umbilical cord blood (UCB)-derived cells. Of these cell types, UCB cells have both ethical and practical advantages; they are readily available, capable of proliferation, and have long telomeres and low immunogenicity (Rogers & Casper, 2004; van de Ven et al., 2007); they may have better effects on gross motor functions (Novak et al., 2016). The use of UCB for treating neurological diseases and brain injury has appreciably increased in recent years (Dessels et al., 2018). Study has already proved that the use of autologous UCB with hypothermia for infants with HIE is feasible (Cotten et al., 2014). However, limited research has focused on the use of UCB to treat PWMI.
Here we review the background, pathogenesis, and pathophysiology of PWMI; summarize the potential effects of UCB cell therapy for PWMI; and discuss the advantages and unresolved issues relating to UCB cell therapy. We also suggest future studies that may help improve the efficacy of UCB cell therapy in preterm infants.
2 PWMI
2.1 Background
PWMI is among the most common causes of various neurobehavioral disorders in preterm babies, and can lead to the development of chronic neurological diseases, such as CP (Volpe, 2009). The basic etiology of PWMI involves brain immaturity, selective vulnerability of white matter, and external insults. The initiating factors are two main insults—hypoxia-ischemia (HI) and infection/inflammation—which have adverse effects on developing brains (Gopagondanahalli et al., 2016). Many fetuses and infants may experience combinations of these insults or repeated insults, potentially inducing injury tolerance or sensitization (Bennet et al., 2018).
The development of brain injury in PWMI is divided into different phases (Fleiss & Gressens, 2012; Gopagondanahalli et al., 2016). In the primary phase, cerebral HI and inflammation are immediately followed by depletion of tissue energy reserves and activation of an array of receptors and ion channels. The subsequent secondary phase involves depletion of high-energy phosphates, cell death, and metabolic disturbances (Iwata et al., 2008; Lorek et al., 1994). Finally, the tertiary phase entails chronic cell injury and repair, and may last for years, likely due to inflammation and epigenetic changes (Fleiss & Gressens, 2012).
Late oligodendrocyte precursor cells (OPCs) are the main cells affected during the PWMI process. The main pathogenesis-initiating mechanisms—HI and/or inflammation—change the growth environment of the brain, making it difficult for late OPCs to survive and differentiate (Galinsky et al., 2018). Mitochondria are at the center of the cellular response to injury in the developing brain (Hagberg et al., 2014).
2.2 Oligodendrocytes
Oligodendrocyte maturation occurs in four sequential stages: OPCs, preoligodendrocytes or late OPCs, immature or pre-myelinating oligodendrocytes, and mature or myelinating oligodendrocytes (Barateiro et al., 2016). The key cellular targets in PWMI are the late OPCs, which are detected during a stage of rapid development between 24 and 40 gestational weeks (Rivkin et al., 1995), and are the predominant oligodendrocyte lineage cells in humans at a gestational age of 24–32 weeks (Back et al., 2001). In the developing brain, OPCs mature, differentiate into immature oligodendrocytes and then into mature oligodendrocytes, and finally wrap the axon to form a myelin sheath, which is important for maintaining axon integrity and supporting quick and efficient signal transmission along the axon (Gopagondanahalli et al., 2016).
Oligodendrocytes and late OPCs have several characteristics that make them sensitive to HI and/or inflammatory injury. Their increased vulnerability to injuries may result from their high contents of iron, lipids, and sphingolipids; low content of reduced glutathione; high oxidative metabolism rate, and the high permeability of glutamate receptors (Mifsud et al., 2014). After insult, NSCs that are enriched in the subventricular zone proliferate and differentiate into OPCs. However, despite the regeneration of a large pool of OPCs, these cells cannot follow the normal trajectory of differentiation and myelination, mainly due to the above-mentioned altered and disadvantageous environment (van Tilborg et al., 2018).
2.3 HI and infection/inflammation
HI and infection/inflammation can have profound adverse effects on white matter development (Elitt & Rosenberg, 2014). HI deprives cells of glucose and oxygen, and thus causes primary energy failure, followed by a cascade of biochemical reactions (Fleiss & Gressens, 2012), ultimately resulting in cell dysfunction and even death. In vitro experiments demonstrate that after 30 min of oxygen-glucose deprivation, 90% of oligodendrocytes will die within 9 hr (Tekkok & Goldberg, 2001). HI can also lead to altered concentrations of signaling proteins and nutrients, for example, brain-derived neurotrophic factor (BDNF), which are essential for normal growth and OPC differentiation in the developing brain (Huang et al., 2018).
Perinatal exposure to infection and/or inflammation is another important cause of preterm birth and PWMI (Goldenberg et al., 2008; Peng et al., 2018). Maternal intrauterine infections (e.g., chorioamnionitis and neonatal sepsis) may lead to systemic inflammation and subsequent neuroinflammation (Anblagan et al., 2016; Grether & Nelson, 1997; Strunk et al., 2014; Zhang et al., 2018) through increased proinflammatory cytokine levels (Gomez-Lopez et al., 2018) and activation of microglial cells in the brain (Zhang et al., 2018). Many studies suggest that HI and infection/inflammation can result in chronic inflammation, gliosis, and epigenetic changes in the long term, thus generating a pathological environment that contributes to failures of oligodendrocyte maturation and neural connectivity (Galinsky et al., 2018).
2.4 Mitochondria
Mitochondria are involved in extensive metabolic functions—including ATP generation, cell death regulation, and biosynthesis—and are essential components for maintaining normal brain development and mediating responses to injuries in the immature brain (Green et al., 2011; Hagberg et al., 2014). Throughout PWMI development, mitochondria play a central role in the cellular response to injuries. The primary phase of HI injury response involves a series of events including tissue energy reserve depletion, cessation of the electron transport chain and ATP generation, disappearance of the H+ concentration gradient across the membrane, and a Ca2+ influx in the depolarized mitochondria (Hagberg et al., 2014). After this primary phase, a few minutes of reperfusion and reoxygenation lead to partial restoration of glucose metabolism and ATP generation in the mitochondria. Although the exact mechanisms of the secondary phase are still under investigation, the consequences may include cell death through either apoptosis or necrosis. The secondary phase is influenced by oxidative stress, excitotoxicity, and inflammation, which determine the severity of tissue damage in different regions of the brain (Arteaga et al., 2015; Fleiss & Gressens, 2012). During this phase, abnormal mitochondria can produce at least 10 times more hydrogen peroxide than usual (Sanderson et al., 2013), leading to oxidative damage. After HI insult, mitochondria release proapoptotic proteins, which elicit cell death by producing apoptosomes and activating downstream caspases (X. Wang et al., 2004). Mitochondria can also trigger innate immune responses, mostly via pattern-recognition receptors (Tannahill & O'Neill, 2011), which may play an important role in the tertiary phase. Overall, mitochondria are critical factors in the immature brain during both health and disease.
3 CURRENT TREATMENT
Optimizing standard perinatal care and basic postnatal supportive care is important for preventing immature brain injury. Additionally, scientists have tested various means of treating PWMI. One of the most promising drugs under investigation is EPO, which can promote angiogenesis, neurogenesis, and gliogenesis in normal brain development. However, trials of EPO in preterm infants show that high-dose EPO treatment does not achieve better neurodevelopmental outcomes or reduce the risk of death at 2 years of age (Juul et al., 2020; Natalucci et al., 2016). Moreover, the effect of EPO seems to depend on the preterm infant's age (O'Gorman et al., 2015; Song et al., 2016).
Cerebral hypothermia reportedly improves neurological outcomes in survivors of perinatal asphyxial encephalopathy (Azzopardi et al., 2009). However, the available clinical data are insufficient and do not verify the safety and benefit of hypothermia in preterm neonates (Herrera et al., 2018). Furthermore, this therapy leads to only slight improvement of long-term outcomes (Laptook et al., 2017; Shankaran et al., 2017). Additionally, melatonin is a potent drug with antioxidative, anti-inflammatory, and antiapoptotic effects (Azedi et al., 2019; Wang et al., 2018); however, clinical studies of melatonin in neonates are lacking.
Human amnion epithelial cells (hAECs) were tested in a preterm fetal ovine brain injury model induced by maternal injection of lipopolysaccharide (LPS), and showed a neuroprotective effect with anti-inflammation and release of trophic factors, resulting in decreased activated microglia and significantly increased numbers of oligodendrocytes and myelin basic protein-positive cells (Yawno et al., 2017). Notably, using mechanical ventilation in preterm infants may cause neuroinflammation and increase the risk of neurological deficits. Thus, hAEC treatment was tested in a ventilated preterm lamb model linked with neuroinflammation, but did not influence neuroinflammation markers (Nott et al., 2020). Clinical data are lacking regarding the use of hAECs for brain injury, particularly PWMI.
Delayed cord clamping by 30–60 s is recommended to decrease the need due to transfusions for anemia, and to lower the risk of necrotizing enterocolitis (Rabe et al., 2012). This simple alteration may improve hemodynamic stability and cerebral autoregulation, and indirectly protect against brain damage (Vesoulis et al., 2019). However, among preterm infants, the combined incidence of death and major complications is not reduced with delayed cord clamping compared to immediate cord clamping (Tarnow-Mordi et al., 2017).
Exogenous stem cells may have therapeutic potential to achieve better outcomes of PWMI, through promotion of angiogenesis, neurogenesis, and synaptogenesis, as well as the release of neurotrophic factors (Fox et al., 2014; Titomanlio et al., 2011). However, tumorigenicity and ethical challenges remain to be solved (Bjorklund et al., 2002; Fleiss et al., 2014). We are currently conducting a study (Grant number 2017YFA0104200) to evaluate the transplantation of human NSC-derived OPCs together with mesenchymal stromal cells (MSCs) or endothelial progenitor cells (EPCs) for PWMI treatment.
Any treatment strategy should be based on the neuropathology of PWMI, and a successful neural restorative therapy must account for the entire neurovascular unit and target both glial and endothelial cells, in addition to OPCs (Lee et al., 2010). Based on this concept, UCB shows great neuroprotective and immunomodulatory potential, as well as the potential to stimulate neural plasticity and regeneration. Next, we will discuss the therapeutic potential of UCB administration to preterm infants.
4 UCB CELLS AS THERAPY
Separated the red blood cells and plasma, UCB mainly comprises regulatory T cells (Tregs), lymphocytes, monocytes and three types of progenitor/stem cells—hematopoietic stem cells (HSCs), MSCs, and EPCs (Jiao et al., 2019; Li et al., 2014; McDonald et al., 2018).
HSCs are multipotent cells that can produce all of the cells present in blood and immune systems throughout the life cycle. It has become a routine clinical therapeutic approach to use HSCs, primarily collected from bone marrow, to treat patients with hematologic diseases (Gluckman et al., 1989; Hu et al., 2018) and metabolic diseases (Cousin et al., 2016). HSCs from UCB have many advantages—including better availability, lower cost, and lower immune rejection responses—and have been used in transplantations for various malignant and nonmalignant diseases (Rocha, 2016). Recent studies show that HSCs are activated and regulated in response to infection and proinflammatory cytokines (e.g., interleukin-1) (King & Goodell, 2011), and can proliferate and be mobilized via direct and/or indirect pathways (Nagai et al., 2006).
MSCs also show the capacity to differentiate or transdifferentiate into various cell types. In vitro studies have proven that MSCs can differentiate into neural cells, but there is less evidence that this would occur in vivo (Dezawa et al., 2004). Upon intravenously entering the body, some MSCs are trapped in the lungs (Tanaka et al., 2018), and the rest MSCs migrate, pass through the blood–brain barrier, and arrive at the injury site through a process called homing (Yagi et al., 2010). When trapped in the lungs, MSCs may increase the level of tissue inhibitor of matrix metalloproteinase-3 in the lungs, which help promote angiogenesis and neurogenesis (Tang et al., 2015). At the injury site, MSCs engage in paracrine signaling and release soluble factors to help initiate progenitor cell proliferation and differentiation, as well as tissue regeneration. The released soluble factors include glial cell line-derived neurotrophic factor (GDNF) (Boku et al., 2013), BDNF (Ramos-Cejudo et al., 2015), epidermal growth factor (EGF), and granulocyte colony-stimulating factor (GCSF) (Rah et al., 2017), which are reported to effectively reduce apoptosis and neuroinflammation; promote angiogenesis, neurogenesis, and synaptogenesis; and reduce gliosis after brain damage. Paracrine activity is mediated by various cytokines, chemokines, extracellular vesicles (EVs) and, more specifically, exosomes that are 70–150 nm in diameter and carry mRNA, microRNA, and proteins (Osier et al., 2018), which transmit the information and help modulate the immune microenvironment (Zhou et al., 2019).
Accumulating evidence from animal models indicates that MSC-EV administration is effective for treatment in many organs, including the liver (Haga et al., 2017), kidney (Zou et al., 2014), and brain (Drommelschmidt et al., 2017; Xin et al., 2013). Both in vitro and in vivo studies show that MSCs can modulate the immune system by suppressing the activities of several cells in the innate immune system and influencing their effector functions (Yagi et al., 2010). Based on these data, MSCs have already been clinically used to treat graft-versus-host disease (GVHD) (Le Blanc et al., 2004, 2008). MSC use has also been explored as a potential treatment strategy for neurological disorders (Yousefi et al., 2017), kidney injury (Sun et al., 2019), lung injury (Xia et al., 2020), and orthopedic injury (Wen et al., 2020).
Mitochondrial transfer from MSCs is an emerging mechanism, which can regenerate and repair damaged cells or tissues (Paliwal et al., 2018). In a rat ischemic stroke model, MSCs can transfer mitochondria to the injured endothelial cells, mainly via a tunneling nanotube like structure, rescuing mitochondrial damage and protecting against oxidative stress (Liu et al., 2019). Similar effects have been found in EPCs and HSCs (Borlongan et al., 2019; Golan et al., 2020).
While the rate of MSC from UCB is low (<0.002% of term UCB) (Jain et al., 2013), MSCs generated from UCB show better proliferation and survival capacities compared to MSCs generated from other sources (Trivanovic et al., 2015).
EPCs are involved in multiple biological activities, particularly in vascular homeostasis, neoangiogenesis, and tissue regeneration (Jia et al., 2019; Peters, 2018). In animal models of ischemia, transplanted EPCs can increase blood vessel density and promote angiogenesis (Li, et al., 2018) through the repair of damaged endothelia or the secretion of trophic factors to stimulate revascularization. EPCs also reportedly promote neurogenesis in the ischemic mouse brain (Li, et al., 2018; Thored et al., 2007). The neuroprotective effects of EPCs involve paracrine mechanisms, including the release of factors and EVs (Esquiva et al., 2018).
Monocytes from UCB play an essential role in mediating the neuroprotective effects, mainly via expressing several secreted proteins (e.g., chitinase 3-like protein-1), and immunoregulation (McDonald et al., 2018; Saha et al., 2019).
Lymphocytes in UCB are largely naïve and less immunologically responsive to alloantigens. Tregs actively suppress other cells in the immune system and in autoimmunity (Sakaguchi, 2004), prevent graft rejection, and regulate immune responses to infection (Sakaguchi, 2005). Since UCB contains naïve lymphocyte and Treg components, UCB transplantation results in a lower incidence of GVHD (Whangbo et al., 2020).
Overall, the available data suggest that UCB cells can play a significant and reproducible neuroprotective role in brain injury due to their anti-inflammatory and immunomodulatory effects, and their ability to stimulate neural plasticity and regeneration. UCB cells may enhance neurological recovery by releasing a range of important neurotrophic factors (e.g., BDNF and IL-6), angiogenic factors (e.g., angiogenin), and other soluble factors (Tsuji et al., 2014). Together, these factors can decrease cell death and neuronal loss, promote endogenous neurogenesis and angiogenesis, and encourage remyelination and neurite outgrowth (Chen et al., 2014; Rosenkranz et al., 2012). In multiple studies, UCB cells have promoted significant improvements of sensory and motor performance (Thomi et al., 2019; Tsuji et al., 2014; Zheng et al., 2018). Therefore, many clinical trials have been initiated to test UCB as a treatment for various neurological disorders (Table 1). Table 2 summarizes several ongoing clinical trials for neurological disorders.
TABLE 1.
Outcomes of clinical trials of UCB interventions for neurological disorders
| Identifier |
Condition |
Treatment |
First registration |
Enrollment |
Primary Outcomes |
References |
| Method |
Route |
Dose (106/kg) |
Short term |
Side effects |
| NCT02397018 |
Ischemic stroke |
Allogeneic UCB |
IV |
5–50 |
03/2015 |
10 |
Improved neurological and functional levels |
No serious adverse events directly related to the study product |
Laskowitz et al. (2018) |
| NCT02176317 |
ASD |
Allogeneic UCB |
IV |
≧10 |
06/2014 |
25 |
Improved social communication skills and reduced symptoms |
N/A |
Carpenter et al. (2019) |
| NCT01147653 |
CP |
Autologous UCB |
IV |
10–50 |
06/2010 |
63 |
Increase in GMFM-66 scores |
Well tolerated and no serious adverse events related to infusions |
Sun et al. (2017) |
| NCT01193660 |
CP |
Allogeneic UCB and recombinant human EPO |
IV |
≧30 |
09/2010 |
105 |
Improved motor and cognitive dysfunction |
No difference in serious adverse effects between the three groups |
Min et al. (2013) |
| NCT00593242 |
Neonatal HIE |
Autologous UCB |
IV |
10–50 |
01/2008 |
52 |
Fresh autologous UCB cells are feasible for use in infants with HIE |
No significant reactions to infusion |
Cotten et al. (2014) |
| N/A |
CP |
Allogeneic UCB |
IV |
N/A |
N/A |
80 |
Observed significant improvements in neurological status and/or cognitive functions |
No acute or delayed adverse reactions |
Romanov et al. (2015) |
| NCT01528436 |
CP |
Allogeneic UCB |
IV/ intra-arterial |
20–60 |
02/2012 |
37 |
Improved muscle strength and gross motor performance |
No serious adverse events |
Kang et al. (2015) |
| NCT01638819 |
ASD |
Autologous UCB |
IV |
≧10 |
07/2012 |
30 |
Improved trends in socialization |
No serious adverse events |
Chez et al. (2018) |
| NCT02256618 |
Neonatal HIE |
Autologous UCB cells |
IV |
N/A |
10/2014 |
6 |
Autologous UCB cell therapy is feasible and safe |
No acute adverse events |
Tsuji et al. (2020) |
| NCT02176317 |
ASD |
Autologous or allogeneic UCB |
IV |
≧25 |
06/2014 |
180 |
UCB administration was safe and well tolerated |
No serious adverse events |
Dawson et al. (2020) |
- Abbreviations: ASD, autism spectrum disorder; CP, cerebral palsy; GMFM, gross motor function measure; HIE, hypoxic-ischemic encephalopathy; IV, intravenous; N/A, not applicable; UCB, umbilical cord blood.
TABLE 2.
Ongoing clinical trials of UCB interventions for neurological disorders
| Identifier |
Condition |
Treatment(s) |
First registration |
Expected outcomes |
| NCT03696745 |
Preterm brain injury |
Autologous UCB stem cells |
10/2018 |
Clinical effect |
| NCT03791372 |
CP |
Autologous UCB |
01/2019 |
Clinical effect and safety |
| NCT02434965 |
HIE |
Autologous UCB and human placental derived stem cells |
05/2015 |
Safety and effectiveness of combination therapy |
| NCT02551003 |
Neonatal encephalopathy |
Autologous UCB and therapeutic hypothermia |
09/2015 |
Neuroprotective effect |
| NCT04243408 |
CP |
Autologous UCB |
01/2020 |
Clinical effect and safety |
| NCT03352310 |
Neonatal HIE |
Autologous UCB |
11/2017 |
Clinical effect |
| NCT02881970 |
Neonatal HIE |
Autologous UCB |
08/2016 |
Clinical safety and feasibility |
- Abbreviations: CP, cerebral palsy; HIE, hypoxic-ischemic encephalopathy; UCB, umbilical cord blood.
5 UCB CELL THERAPY AND PWMI
The main downstream mechanisms of HI that lead to PWMI are oxidative stress and excitotoxicity, which are considered the foundation of HI-induced damage to neurons. HI injury rapidly induces free radical production and overstimulates excitatory amino acid receptors, and both of these actions are related to oxidative stress and excitotoxicity (Lai et al., 2014; Qin et al., 2019). Characteristics of the immature brain make it particularly vulnerable to oxidative damage—including its high oxygen consumption, high Fe2+ content, high level of water, easy oxidation of unsaturated fatty acids, and underdeveloped antioxidant system (Qin et al., 2019). Research has shown that MSCs can reduce oxidants and radicals, and help combat oxidative stress. MSCs can also reduce cell apoptosis by regulating the Nrf2-Keap1-ARE signal pathway, which is related to H2O2-induced oxidative injury (Yan et al., 2019). MSC-EVs can also alleviate oxidative stress by delivering antioxidant enzymes, such as manganese superoxide dismutase (Harrell et al., 2019; Yao et al., 2019). Mitochondrial transfer from MSCs into injured cells can reduce mitochondrial dysfunction induced by oxidative stress (Burt et al., 2019; Li, et al., 2018). In a rodent epilepsy model, MSCs exhibit the ability to protect against glutamate excitotoxicity by reducing excessive stimulation of N-methyl-D-aspartate (NMDA) receptors and Ca2+ overload (Papazian et al., 2018). UCB contains some amount of MSCs, but it remains unclear whether UCB cell administration can suppress oxidative stress and excitotoxicity.
UCB may help prevent PWMI via the anti-inflammatory and immunomodulatory abilities of MSCs, Tregs, and lymphocytes. Additionally, UCB cells can produce several neurotrophic factors (e.g., BDNF, GCF, and EGF) that promote tissue repair. Upon transplantation, UCB cells migrate to the injured site within 24 hr via activated CXCR4 (Rosenkranz et al., 2010), a stromal cell-derived factor 1 receptor that is mainly expressed in glial cells and is increased in the brain after HI injury. UCB cell therapy has shown some effectiveness in animal models of PWMI. In fetal sheep with HI-induced preterm brain injury, intravenously administered UCB cells exhibited high efficacy in protecting white matter through anti-inflammatory effects. Moreover, early administration of UCB within 12 hr post-HI achieved better effects than administration at 5 days post-HI (Li et al., 2016). UCB administration reportedly protects the cerebral white matter of preterm fetal sheep from systemic maternal LPS exposure, likely through anti-inflammatory effects (Paton et al., 2018). Both term cord blood and preterm cord blood cells can reduce HI-induced PWMI in fetal sheep, mainly by suppressing inflammation. However, it appears that term and preterm cord blood cells have different subordinate neuroprotective mechanisms (Li et al., 2017). In fetal sheep with inflammation-induced brain injury, triggered by intravenous injection of LPS at 0.65 gestation, experimental data showed that compared to MSCs alone, UCB (containing MSCs and other cell types) promoted a better outcome in terms of preterm white matter development (Paton et al., 2019).
UCB can also restore the number of oligodendrocytes. During in vitro oxygen-glucose deprivation, UCB administration directly protects cultured oligodendrocytes (Hall et al., 2009). In a fetal sheep model of maternal LPS-induced preterm brain injury, UCB administration restored total and mature oligodendrocytes compared to no treatment (Paton et al., 2018). Moreover, in a mechanistic study in animal models of middle cerebral artery occlusion, intravenously injection of human UCB cells at 48 hr post-injury yielded increased Akt phosphorylation and peroxiredoxin 4 protein expression in oligodendrocytes, and decreased proteolytic cleavage of caspase 3, promoting oligodendrocyte survival (Rowe et al., 2012). In HI-exposed rats, treatment with UCB cells increases the proportion of mature oligodendrocytes and improves myelination in cortical areas (Zhang et al., 2019). Finally, in mice exhibiting cuprizone feeding-mediated demyelination, intracranial injection of a cell therapy product from banked human UCB leads to enhanced myelination, an increased proportion of fully myelinated axons, decreased gliosis, and an increased number of proliferating oligodendrocyte lineage cells (Saha et al., 2016). Together, these findings suggest that UCB may prevent PWMI and promote oligodendrocyte survival, differentiation, and myelination.
In addition to protecting oligodendrocytes, UCB can also help improve the environment of the neurovascular unit. UCB cells can promote angiogenesis and restore blood–brain barrier integrity, likely via angiogenic factors and EPCs. In a rat traumatic brain injury model, the administration of UCB cells at 72 hr post-injury restored blood–brain barrier integrity (Srivastava et al., 2019). UCB cells can also decrease astrocyte differentiation and increase newborn neurons in neonatal HI rats, thus alleviating brain injury (Wang et al., 2013, 2014; Zhang et al., 2019). Overall, UCB cells possess anti-inflammatory and immunomodulatory abilities and secrete a variety of important trophic factors, which may improve the environment for OPC maturation and myelination.
6 ADVANTAGES OF UCB CELL THERAPY
UCB, a material that used to be discarded, has become widely used in clinical practice for hematopoietic malignancies (Maung & Horwitz, 2019), marrow failure (Yao et al., 2014), immunodeficiency disorders (Knutsen & Wall, 2000), cardiac diseases (Roura et al., 2014), endocrinological disorders (Reddi et al., 2015), and neurological diseases. Compared with other therapies, UCB cell therapy has many advantages related to its collection, storage, and safety. Noninvasive UCB collection presents no risks to the mother or infant (Donaldson et al., 2000; Valle et al., 2017). Moreover, UCB cell procurement and use do not raise the ethical concerns that surround embryonic and fetal tissues (Jaing, 2014). UCB can be stored at cryogenic temperatures (Wu et al., 2019), which maintain its optimal viability and are convenient for use and shipping (M-Reboredo et al., 2000). Several years ago, UCB banks were established as alternative sources of hematopoietic stem and progenitor cells for HSC transplantation (Dessels et al., 2018; Roura et al., 2015). The safety of UCB administration was first demonstrated when a 5-year-old child with Fanconi anemia received UCB treatment in 1988 (Gluckman et al., 1989). Since then, over 40,000 allogeneic transplants using UCB have been performed in both children and adults (Mayani et al., 2020), and the studies listed in Table 1 indicate no serious adverse events related to UCB administration.
Unlike cell therapy utilizing a single cell type, UCB cell therapy involves multiple cell types with various functions—including anti-inflammatory and immunomodulatory activities, and the ability to stimulate neural plasticity and regeneration (Paton et al., 2019). These advantages suggest that UCB administration may serve as a promising strategy for PWMI treatment.
7 UNSOLVED ISSUES RELATED TO UCB CELL THERAPY FOR PWMI
There is increasing interest in identifying the neuroprotective effects of UCB in PWMI. However, several factors affect the clinical use of UCB.
7.1 UCB administration time and dose
Concerning the time of UCB administration, studies in animal models suggest that early UCB intervention—before or during the secondary phrase—is essential for protecting white matter structures and suppressing cerebral inflammation (Aridas et al., 2016; Li et al., 2016). However, early diagnosis of PWMI is difficult, and it is thus challenging to administer UCB for PWMI prevention and early treatment. Moreover, for allogeneic UCB transplantation, time is required to thaw and wash the UCB cells, which may decrease the efficacy of UCB for preventing and treating PWMI.
The appropriate dose of UCB cells for preterm infants also remains elusive. Previous studies have suggested that doses of 1–5 × 107 UCB cells/kg may have neuroprotective effects, and can be safely transfused into neonates or children for the treatment of neurological disorders (Carpenter et al., 2019; Cotten et al., 2014; Sun et al., 2017). However, this regimen may not be suitable for preterm infants due to the complex characteristics of immature brains. It remains unclear whether the recommended dose of UCB cells may be too high for preterm infants and increases mortality (Wasielewski et al., 2012) or is too low and has a poor therapeutic effect (de Paula et al., 2012). Additional research on the clinical use of UCB for PWMI is needed to address these questions.
7.2 Prenatal factors
UCB is significantly affected by prenatal factors. Research shows that UCB quality and quantity can be influenced by maternal body mass index (Al-Sweedan et al., 2013), parity (Manegold-Brauer et al., 2014), maternal age (Page et al., 2014), and maternal diseases or pregnancy complications (Al-Sweedan et al., 2013). Moreover, different prenatal factors may slightly alter the UCB cell components. For example, HSC count decreases by 17% with each additional birth (Ballen et al., 2001), meaning that some samples may not contain sufficient UCB cells to elicit a positive initial clinical outcome (Rich, 2015). To address this problem, physicians evaluate UCB cells based on total nucleated cell (TNC) counts (Rich, 2015). It is assumed that higher TNC counts will yield better clinical outcomes.
7.3 Autologous versus allogeneic UCB
It has been shown that both term and preterm UCB cells can reduce HI-induced PWMI (Li et al., 2017). However, three factors limit the use of autologous UCB in preterm infants. First, compared to term UCB collection, preterm UCB collection is much more difficult. Complex preterm prenatal factors result in lower UCB quantities, such that the retrieved autologous UCB may be insufficient for PWMI treatment (Peng et al., 2020). Second, delayed cord clamping has been recommended for the care of vigorous preterm neonates (Aliyev & Gallo, 2018), but this practice decreases the TNC counts of the collected UCB units (Allan et al., 2016). Third, children born preterm may be diagnosed with CP substantially after birth, and not have stored autologous UCB cells available for treatment (Mazzoccoli et al., 2016). For these reasons, allogenic UCB seems to be more clinically feasible and applicable. One study has demonstrated the apparent safety and feasibility of the transfusion of allogeneic UCB red blood cell concentrates into preterm infants (Bianchi et al., 2015). However, there remains a need for thorough investigations of the safety and clinical use of allogeneic UCB for treating PWMI.
8 FUTURE PERSPECTIVES
First, the possibility of expanding specific cell types has attracted scientific attention, and may solve the problem of limited UCB cell sources (Pineault & Abu-Khader, 2015). Most protocols for UCB cell expansion rely on culturing with specific cytokines that do not alter the main properties or therapeutic potentials of UCB cells (Berglund et al., 2017; Mennan et al., 2019). Each of the above-described UCB cell types exhibits individual characteristics that differentially contribute to neuroprotection and regeneration in PWMI.
Second, greater clinical outcomes have been achieved by using combined therapy. Combination therapy may have better effectiveness, with each component complementing the shortcomings of the other treatments. Future studies should test the administration of UCB plus other therapies to obtain better outcomes in PWMI.
Third, long-term PWMI treatment may be administered through multistage UCB cell therapy. To date, PWMI treatment strategies have been concentrated at or before the secondary phase with the aim of rescuing a large number of neurons. However, recent findings suggest that the therapeutic window could extend beyond the secondary phase, and that long-term treatments could mitigate chronic inflammation or plasticity (Hagberg et al., 2014). Studies have proven that UCB can improve motor and cognitive dysfunction in children with CP, whose age between 6 months and 20 years (Kang et al., 2015; Romanov et al., 2015). It would be beneficial to establish a multistage UCB cell therapy for the clinical treatment of PWMI. Notably, UCB administration during the primary and secondary phases of insult will rescue more neurons and oligodendrocytes; and repeating UCB administration in the tertiary phase of insult could regulate inflammation and trigger tissue repair.
9 CONCLUSIONS
Substantial evidence from animal models and clinical studies suggests that UCB cell therapy offers a promising therapeutic approach for PWMI, based on the UCB cell functions of anti-inflammation, immunoregulation, neuroprotection, and regeneration. However, multiple issues remain to be resolved. Due to the heterogeneous injuries and the complexity of the immature human brain, PWMI in animal models cannot fully represent the characteristics of human PWMI. Thus, the experimental results obtained from animal models must be considered with caution. To date, very few studies have examined the long-term consequences of UCB cell therapy for PWMI. Therefore, there remains a need for additional studies, including clinical investigations, to determine the safety, optimal dose, administration time window, and long-term consequences of UCB cell therapy.
DECLARATION OF TRANSPARENCY
The authors, reviewers and editors affirm that in accordance to the policies set by the Journal of Neuroscience Research, this manuscript presents an accurate and transparent account of the study being reported and that all critical details describing the methods and results are present.
ACKNOWLEDGMENTS
This work was supported by National Key Research and Development Program of China Stem Cell and Translational Research (2017YFA0104200).
CONFLICT OF INTEREST
All authors have no conflicts of interest to declare.
AUTHOR CONTRIBUTIONS
Conceptualization, L.W. and H.Q.; Writing – Original Draft, H.Q., T.Q. and T.W.; Writing – Review and Editing, X.W., C.Z., C.C. and L.W.; Supervision, L.W.; Funding Acquisition, L.W.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
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