Even in the current era of advances in immunotherapy and targeted therapy for various malignancies, hematopoietic stem cell transplantation (HSCT) remains a mainstay of treatment for various benign and malignant conditions. Traditionally, the source of these hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) has been primarily from the bone marrow or from mobilized peripheral blood. In the United States alone, over 8500 HSCTs are performed each year (www.Cibmtr.org). Despite the increasing incidence of HSCT utilization, there remain several challenges regarding optimal matching of patients and donors. Although the likelihood of failing to locate a human leukocyte antigen (HLA)-matched donor for a White patient is approximately 25%, the likelihood of failing to locate a suitable HLA-matched donor for most other ethnic and racial groups is substantially higher, with only a less than 20% likelihood of locating an adequate match in African-American patients [1–3]. Furthermore, for those patients in urgent need of transplantation, it is not feasible to wait what is often several weeks to locate a potential match . These challenges and others have led to interest in alternate sources of HSC.
The first HSCT using HSC derived from umbilical cord blood was performed in Paris, France in 1988 in a patient with Fanconi anemia (REF). Since that time, numerous advances have been made in this constantly evolving field [5,6]. Cord blood is an attractive alternative to bone marrow or peripheral blood sources of HSC or HPC given that it is readily available for use; collection is achieved with ease; and there is a lower incidence of graft vs. host disease. Additionally, the use of cord blood allows for increased HLA-mismatch disparity, which in turn widens access of potentially curative treatment to individuals without an HLA-matched donor [2,7,8–12]. However, the utilization of cord blood for HSCT has been fraught with challenges as well. For example, when compared with bone marrow or peripheral blood HSCT, cord blood HSCT has a higher propensity for graft rejection, failed or delayed engraftment of platelet and neutrophils, and as a result, cord blood HSCT has been associated with an increased risk of transplant-associated complications [2,5,6,7,8,10,13▪,14]. Many of the limitations of cord blood HSCT stem from the lower yield cell dose available for transplantation when using cord blood as a donor source rather than bone marrow or PD. This in turn leads to delayed neutrophil and platelet engraftment and delayed immune reconstitution [6,14–17].
Attempts to improve outcomes in recipients of cord blood HSCT have led to discoveries and advancements tailored not only to increasing the number of cells collected but also in techniques to improve homing mechanisms of these cells to the bone marrow niche. In this report, we describe some of the techniques that have been and are currently being utilized to improve outcomes in recipient of cord blood HSCT. Additionally, we seek to explore novel concepts currently in development.
HOW CAN WE INCREASE CELL YIELD?
When compared with bone marrow and peripheral blood, cord blood yields less than 20% of the requisite cell dose needed for transplantation [4,15,17–19]. Transplantation using two cord blood units has been explored as a technique to increase graft cell dose, and although most institutions still utilize double rather than single cord units for transplantation, this technique alone did not significantly improve time to engraftment [18–20]. In an effort to further increase the overall cell yield of HPC and HSC from cord blood, there has been an interest in the ex-vivo expansion of cord blood units prior to infusion [21–23].
Ex-vivo expansion techniques
Many ex-vivo expansion approaches have been utilized such as the use of cytokines, blockage of in-vivo early progenitor cell (EPC) differentiation, and more recently, coculturing with mesenchymal progenitor cells (MPCs).
Understanding the microenvironment and the stem cell niche
HSCs exist within a complex network of connective tissue and cells, such as stromal cells, within the stem cell niche or microenvironment. The interaction of HSCs with these stromal cells and the microenvironment leads to the paracrine secretion of growth factors and cytokines that ultimately control the differentiation and proliferation of the HSCs [2,8,13▪,24]. In recent years, there has been much interest into the recreation of the stem cell niche in an effort to optimize HSC expansion. Various techniques have been developed with the goal of expanding HSCs that maintain their “stemness" without activation of differentiation pathways [2,8,13▪].
The use of cytokines
Static culture techniques, whereby CD34+ cells from cord blood are cultured in media with stem cell factor, megakaryocyte growth and differentiation factor, and granulocyte colony stimulating factor have in fact led to proliferation of CD34+ cells; however, this technique failed to significantly improve neutrophil and platelet engraftment [2,8,23]. Continuous perfusion culture devices that maintain optimal culture conditions have also been employed and failed to either robustly increase the number of CD34+ cells or to improve time to engraftment. Additionally, graft failure occurred in three of 27 patients transplanted with cord blood units developed using continuous perfusion cultures [2,8,25].
Early progenitor cell differentiation blockade
A potential explanation for the rather disappointing results of cultures supported with cytokines alone is the fact that although the utilization of cytokines expanded the total cell yield, this technique led to the loss of EPC via the differentiation of CD34+ cells into mature cells. Therefore, various agents (copper chelation and nicotinamide) and techniques (alterations of Notch signaling aryl hydrocarbon receptor antagonism) have been deployed to halt differentiation of CD34+ cells in vitro. [2,6,26–30]. For example, the aryl hydrocarbon receptor antagonist StemReginin1 (SR1) allows for proliferation (expansion) but not differentiation of CD34+ cells. A phase I/II study of cord blood expansion using SR1 resulted in more than-300 fold increase in the expansion of CD34+ cells and a shorter median time to engraftment; 11 days vs. 23 days in unmanipulated units [2,11]. Interestingly, two patients in this study who received only a single SR1-expanded cord blood unit rather than double cord blood transplant (DCBT) experienced shorter engraftment periods (<12 days), an observation which led to the possibility of single expanded cord blood unit transplantation . Though each of these EPC differentiation blockade techniques has advanced the field in some capacity and has increased the yield of CD34+ cells, various challenges remain, such as cost and feasibility.
During expansion, a major concern is selective expansion of short-term reconstituting HSC at the expense of long-term reconstituting HSC, which can reduce long-term graft viability despite evidence of early hematopoietic recovery [31,32]. There are no surrogate markers that define HSC and HPC ex vivo, which is a challenge when assessing long-term HSC activity in expanded cultures. Tracking of HSC activity in vivo has been challenging as cell surface markers can change when in culture. Fares et al. has demonstrated that UM171, a pyrimidoindole derivative, led to in-vivo HSC expansion. Further evaluation revealed that UM171 treatment stimulated gene expression of endothelial protein C receptor (EPCR), which has been shown to regulate long term (LT)-HSC retention in the bone marrow . They later demonstrated that in UM171-treated cultures, and to a lesser extent in untreated cultures, EPCR represents a marker for expanded LT-HSC. Using EPCR as a marker to monitor HSC activity, they determined that EPCR monitoring could also represent a surrogate to predict expansion levels of cord blood-derived HSC. The authors note that further analysis of the transcription factors that contribute the self-renewal of EPCR+ cells could ultimately lead to therapeutic advancements in the future .
Mesenchymal progenitor cell-supported expansion
One technique developed to simulate the stem cell niche is the use of coculture with MPCs. MPCs are a subset of undifferentiated cells that comprise the stroma of the stem cell niche. These cells have a critical role in the proliferation, differentiation, and homing of HSCs via the secretion of cytokines such as IL-6 and stem cell factor [2,7,8,13▪,34]. MPCs have minimal major histocompatibility complex (MHC) class II expression and lack various costimulatory molecules necessary for T-cell-mediated immune responses. As a result, MPCs do not stimulate alloreactive T cells, which makes them an attractive source in allotransplantation. Another attractive feature of MPC coculture is that, unlike most other techniques for cord blood expansion, this technique eliminates the need for selection of HSC and HPC on the basis of CD34 or CD133 expression [2,7].
A landmark study by de Lima et al. evaluated 31 patients who received DCBT composed of one unit of cord blood cells expanded ex vivo in MPC cocultures and one unit of unmanipulated cord blood. This study demonstrated the efficacy and safety of cord blood expanded utilizing mesenchymal stem cell (MSC) coculture. There was a higher incidence of engraftment (96 vs. 78%) and an overall shorter time to neutrophil engraftment (15 days vs. 24 days) compared to DCBT using unmanipulated cord blood. Additionally, there was no difference in the expansion responses between MPCs obtained from family members vs. those obtained “off the shelf." This is a particularly appealing feature for patients with rapidly progressing disease who cannot spare the additional time required to obtain MPCs from a family source . In most of the prior studies conducted using MSC coculture in cord blood HSCT, patients were treated with myeloablative conditioning regimens. However, these regimens pose challenges when treating older patients or patients with comorbidities. Mehta et al. recently demonstrated efficacy using reduced intensity rather than myeloablative conditioning regimens. The group demonstrated that in patients who received reduced intensity conditioning regimens, the infusion of one MPC-expanded umblical cord blood (UCB) unit and one unmanipulated UCB unit led to shorter time to neutrophil engraftment compared with those who received two unmanipulated UCB units [13▪].
Wharton's jelly mesenchymal stromal cells
Given that the microenvironment within the umbilical cord and placenta, the source of cord blood HSCs and HPCs, differs from that of the bone marrow, there has been interest in the development of culture techniques that better mimic that of the placenta stem cell niche. The umbilical cord itself is not an optimal source for MSC collection, but MSCs from the Wharton's Jelly component of the cord (WJ-MSC) are useful in cord blood HSC expansion [34–36]. WJ-MSCs express the same cell markers as MSCs obtained from the bone marrow, but they also express additional molecules necessary for interaction with and expansion of HSCs, such as granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, and CD117 . This advantageous feature makes WJ-MSC a favorable source for MSCs needed to serve as a feeder layer during the process of coculture [34–36]. Indeed, various studies have evaluated this concept. Magin et al. compared three sources of cells serving as feeder layer for coculture: bone marrow MSC, WJ-MSC, and human umbilical cord vein endothelial cells. Although the authors noted that each of these options could potentially serve as viable source for a feeder layer to expand cord blood HSCs, the most favorable results were noted with WJ-MSCs followed by bone marrow-MSC and then human umbilical cord vein endothelial cells [37,38].
Hypoxia and metabolism
HSCs naturally reside in hypoxic environments with oxygen tension of 1–6% within both the bone marrow and the umbilical cord [24,39,40]. It is well established that hypoxia maintains the “stemness” of HSCs; therefore, there has been much interest utilizing this principle to optimize ex-vivo expansion by protecting HSCs and HPCs from extraphysiologic oxygen shock/stress. Various studies have demonstrated that the expansion of HSCs is in fact improved when collected and grown under hypoxic conditions, and many additional studies have evaluated which of the various stem cell pathways are activated and inhibited by hypoxia [24,39,40,41▪,42,43]. There have since been numerous translational investigations targeting the manipulation of these pathways to optimize expansion. For example, when collected in hypoxic conditions, some studies note a threefold to fivefold increase in the number of HSCs obtained [39,40,43]. A recent study by Zhao et al. solidified this finding and also notes that hypoxia increases vascular endothelial growth factor secretion and activates pathways such as Notch, Wnt, and Hedgehog. These pathways affect hypoxia-inducing factor, which is important in maintaining HSCs in the quiescent and undifferentiated state and allows the transition from oxidative phosphorylation to glycolysis [24,41▪,44]. These findings suggest that optimal collection and expansion of cord blood HSCs would be best performed under hypoxic conditions; however, this is currently a very cumbersome process that is logistically complex. The challenge now is to discover techniques that are more efficient and cost-effective.
Though these previous studies demonstrated the idea that hypoxia may improve cord blood HSC proliferation, a growing body of evidence supports the idea that hypoxia may be detrimental to homing and differentiation via increased erythropoietin (EPO) signaling pathways [43,45▪,46▪]. EPO is produced in response to hypoxia, and the bone marrow microenvironment is important in the metabolism and clearance of EPO. Therefore, EPO levels increase as a result of bone marrow-conditioning regimens used prior to SCT. Aljitawi et al. [43,45▪] recently noted that approximately 20% of cord blood HSCs and HPCs express EPO receptors, and exposure of cord blood HSCs to EPO led to decreased migration toward homing chemokines. Additionally, the group reports on their experience with the utilization of hyperbaric oxygen as a method reducing EPO prior to HSC infusion. In a small phase I study, the group demonstrated improved results in patients who received reduced intensity-conditioning regimens and received hyperbaric oxygen treatments prior to cord blood HSCT. These patients demonstrated shorted time to recovery of both neutrophils and platelets, and a shorter period of transfusion dependency [43,45▪].
Many additional novel approaches for ex-vivo cord blood expansion have targeted the glycolytic activities of HSCs and HPCs. The hypoxic environments of the bone marrow niches to where these cells home prevent oxidative phosphorylation; therefore, glycolysis is the primary pathway utilized. Prior studies demonstrated the importance of the glycolytic pathway in HSC expansion and prevention of differentiation. Recent work by Guo et al. [41▪,42] demonstrated that peroxisome proliferator-activated receptor γ antagonism promotes HSC and HPC engraftment and self-renewal via upregulation of glycolytic pathways, and therefore, differentiation is decreased.
Further work by Guo et al. led to an improved understanding of the metabolic pathways of HSCs through regulation via nuclear hormone receptors. Nuclear hormone receptors are activated by various hormones such as vitamin D, estrogen, glucocorticoids, and retinoic acid. Guo et al. [41▪,42] demonstrated that modulation of these pathways via antagonists or agonists of the nuclear hormone receptors can be beneficial in the enhancement of HSC and HPC engraftment [44,47,48]. For example, antagonism of the retinoic acid receptor pathway inhibits HSC differentiation and promotes HSC expansion and engraftment [42,47]. Additionally, studies in murine models have demonstrated that engraftment and homing capabilities can be enhanced via pretreatment of HSCs and HPCs with glucocorticoids [41▪,42].
These discoveries have important implications for future studies targeting transcriptional regulation via nuclear hormone receptor modulation in an effort to enhance engraftment in cord blood HSCT.
Various other strategies have been used to enhance the homing capacity of cord blood HSCs and HPCs. A critical part of homing is appropriate interaction of the transplanted cells with various adhesion molecules such as selectins. Poor fucosylation of selectin ligands has been implicated as one factor contributing to decreased homing. In a first-in-human trial, Popat et al.  demonstrated that ex-vivo fucosylation of CD34+ cord blood cells in patients receiving double cord blood HSCT led to decreased time to engraftment of both neutrophils and platelets when compared with historical controls. Various other techniques such as treatment with prostaglandin E2 derivatives and inhibitors of dipeptidyl peptidase 4 have led to promising results, though a detailed discussion is beyond the scope of this review [50,51]
Even with the numerous techniques described above, as well as many others that are beyond the scope of this discussion, there is still no “gold standard" strategy that has definitely solved the challenge of maintaining HSCs self-renewal and stemness properties after long-term expansion. Fabrication of nanofiber scaffolds that mimic the intrinsic conditions of HSC stem cell niche have been developed way to promote expansion. These scaffolds attempt to recreate specific components of the extracelluar matrix such as structural, mechanical, and cellular properties of the native stem cell microenvironment. These techniques, though promising, are tedious and costly. Additionally, it is important to further understand how the materials used in these models may alter the properties of the expanded HSC. For these reasons, there is now an increased focus on 3D scaffolding and other techniques to make this process more efficient and cost-effective .
Cord blood is an attractive source for HSC collection, and though there are many benefits over bone marrow or peripheral blood transplant sources, cord blood HSCT has various challenges. There have been numerous exciting advances in this field in recent years, but there are still many unanswered questions that will require further investigation. In addition to the novel ideas described above regarding ex-vivo expansion of HSC, there have been advances using ex-vivo expansion techniques to modulate adaptive immunity, with natural killer cell expansion and now techniques combining antiviral immunotherapy and chimeric antigen receptor T cells as examples. The challenge is now how to optimize the process of cord blood HSCT such that advances in ex-vivo expansion and modulation of homing mechanisms can be streamlined and reproduced. Though the above advances have been studied largely as isolated techniques; additional trials are needed to determine the ideal combination of techniques that will yield the most promising outcomes while balancing efficiency, efficacy, reproducibility, and cost.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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