**1. Introduction**

Allogeneic transplantation is the only curative approach for many hematologic malignant and nonmalignant disorders. Unfortunately, only 30% of patients will have a matched sibling donor [1]. However, well-matched donors (MUDs) are a suitable alternative for those who do not. In one study, well-matched MUDs were identified in 53% of those with Northern European ancestry, compared to only 21% of patients of other origin [2]. For patients without a histocompatible adult donor, transplant options include unrelated umbilical cord blood (UCB) transplantation or transplant from a haploidentical (haplo) donor [3]. Since the first successful UCB transplant in 1988 [4], UCB has been used as a graft source for over 40,000 patients with both malignant and nonmalignant diseases [5, 6].

As a graft source for transplantation, UCB has several practical advantages including ease of procurement, absence of donor risks, reduced risk of transmissible infections, and availability for immediate use [7]. UCB is also associated with a lower incidence of graft-versus-host disease (GVHD) despite HLA disparity [8]. Therefore, UCB extends the application of allogeneic transplant to ethnic minority populations who are underrepresented in donor registries [9]. Additionally, UCB transplantation is associated with reduced leukemia relapse in patients with evidence of minimal residual disease at time of transplant, suggesting a strong graft-versus-leukemia effect [10]. However, UCB units in themselves are limited in

#### **Figure 1.**

*Hematopoietic stem/progenitor cell (HSPC) homing to the bone marrow. This process is mediated by CXCR4 receptors on the surface of HSPCs and stromal cell-derived factor-1 (SDF-1) in the bone marrow.*

cell doses available for optimal transplantation in adults. UCB stem cells also demonstrate defects in homing to the bone marrow (BM), implicating delayed recovery of neutrophil and platelet count and achieved engraftment, resulting in higher rates of graft failure [11]. This prolonged time to engraftment is also associated with delayed immune reconstitution after UCB transplantation [12–14], resulting in higher posttransplant infection rates [15]. Strategies to overcome these defects in homing and engraftment are clearly needed in order to make this potentially curative therapy more effective for patients. Additionally, such strategies might apply to other types of hematopoietic stem cell (HSC) transplantation, including autologous stem cell transplantation as well as allogeneic stem cell transplantation.

Homing is the first process by which circulating hematopoietic cells actively cross the blood/BM endothelium barrier to migrate into the BM compartment (**Figure 1**) [16]. This process is fairly rapid and occurs within hours and no longer than a day or two after stem cell infusion [16]. HSC homing is mediated in part by the binding of chemokine CXCR4 receptor on the surface of HSCs to their ligand, stromal cell-derived factor-1 (SDF-1) expressed by BM stromal cells [17]. Stem cell homing precedes engraftment, corresponding to proliferation and differentiation of hematopoietic stem cells (HSCs) to produce mature, functional hematopoietic cells within the BM [18]. One study claimed that only 18–20% of all intravenously transplanted stem cells, including different subsets, seeded in the BM, with UCB stem cell seeding even lower [19]. Another study demonstrated that human UCB stem cell seeding efficiency in NOD/SCID mice was found to be less than that for BM (4.4% versus 20%) [20].

#### **2. Current methods to improve UCB HSPC homing**

Due to the curative potential of UCB transplantation, several approaches have been investigated to improve UCB stem cell homing to the BM. In one study inhibition of CD26 peptidase activity by pretreating purified CD34+ human CB cells with

**153**

*Effect of Hyperbaric Oxygen on Hematopoietic Stem Cell Transplantation*

Diprotin A significantly enhanced engraftment of HSCs from human UCB into NOD/SCID mice [21]. A CD26 peptidase inhibitor, sitagliptin, was investigated in a clinical trial with encouraging results in engraftment of adults with hematological malignancies after using a single unit UCB transplant [22]. Another strategy taken involved direct intrabone administration of cord blood cells into the superiorposterior iliac crest under rapid general anesthesia. Though this strategy produced impressive results in one study [23], another study showed contradictory results [24]. Therefore this procedure has not been widely accepted. In exploring further defects in cord blood stem cell homing, it was found that cord blood CD34+

have reduced alpha(1,3)-fucosyltransferase (FucT) expression and activity causing a depletion of cord blood stem cell surface ligands necessary for interaction with adhesion molecules at time of stem cell homing [25]. Forcing fucosylation was found to be clinically feasible with encouraging engraftment efficiency data in the double UCB transplant setting [26]. Some of these interventions require significant logistical support, and some require graft manipulation; accordingly, there is an urgent need to identify safe and practical interventions to enhance UCB homing and engraftment for patients with hematologic malignancies who are undergoing

**3. Pre-clinical data supporting HBO role in modulating EPO/EPOR** 

Previously published work implicating erythropoietin (EPO) in HSC homing led investigators to examine the role of EPO/EPOR signaling in HSC homing and engraftment in vitro and in vivo pre-clinical models. Gonzalez et al. demonstrated that circulating HSCs rapidly decline after birth [27]. Interestingly, the decline in HSCs correlated with low EPO blood concentration. Additionally, the decline in HSCs being attributed to HSC BM homing, these observations suggested a possible role for EPO in BM homing and clearance of HSCs from the infant's circulation following birth. Investigators have pursued HBO as a potentially safe approach to effectively lower EPO as previously published [28]. The hypothesis was that lowering EPO at the time of hematopoietic stem/progenitor cell (HSPC) infusion will result in improved bone marrow homing and subsequent engraftment. Studies examining HBOT effects on hematopoietic stem cells are limited. On the other hand, HBOT has been shown to have minimal, if any, effects on blood counts during steady-state conditions [29]. The previously published and accumulated pre-clinical data that supports EPO's role in UCB engraftment are summarized in

by flow cytometry. Analyses of 5 UCB units revealed that on average 6.5% of CD34+ UCB cells express EPOR [30]. A significantly higher percentage of EPOR positive

To test whether a functional EPO-EPOR signaling cascade was activated in EPOR-

(RNAi), and the erythroid differentiation potential after culture in methylcellulose

Depletion of EPOR expression by RNAi greatly reduced the size of erythroid colo-

ing that EPO promotes functional EPO-EPOR signaling response in these cells [30].

cells) population. EPOR positive cells were less among

cells, EPOR expression was depleted via RNA interference

differentiation potential toward the erythroid lineage, indicat-

cells (45.7 ± 1.4%, **Figure 2**) was observed within the HSC (Lin<sup>−</sup> CD34+

cells

, the expression of EPOR was assessed

CD38<sup>−</sup> CD45RA<sup>−</sup> CD90<sup>−</sup> CD49f<sup>−</sup> cells,

CD38+

cells without EPOR depletion.

CD38<sup>−</sup>

cells, 25.1 ± 0.7%).

*DOI: http://dx.doi.org/10.5772/intechopen.85223*

allogeneic stem cell transplantation.

**signaling in HSCs**

the next section [30].

CD45RA<sup>−</sup> CD90+

expressing UCB CD34+

nies and UCB CD34+

To understand EPO effects on UCB CD34+

CD49f+

multipotent progenitor (MPP) (Lin<sup>−</sup> CD34+

culture medium was compared to UCB CD34+

22.2 ± 0.3%) or the broader progenitor pool (Lin<sup>−</sup>CD34+

*Effect of Hyperbaric Oxygen on Hematopoietic Stem Cell Transplantation DOI: http://dx.doi.org/10.5772/intechopen.85223*

*Advances in Hematologic Malignancies*

cell doses available for optimal transplantation in adults. UCB stem cells also demonstrate defects in homing to the bone marrow (BM), implicating delayed recovery of neutrophil and platelet count and achieved engraftment, resulting in higher rates of graft failure [11]. This prolonged time to engraftment is also associated with delayed immune reconstitution after UCB transplantation [12–14], resulting in higher posttransplant infection rates [15]. Strategies to overcome these defects in homing and engraftment are clearly needed in order to make this potentially curative therapy more effective for patients. Additionally, such strategies might apply to other types of hematopoietic stem cell (HSC) transplantation, including autologous

*Hematopoietic stem/progenitor cell (HSPC) homing to the bone marrow. This process is mediated by CXCR4* 

*receptors on the surface of HSPCs and stromal cell-derived factor-1 (SDF-1) in the bone marrow.*

Homing is the first process by which circulating hematopoietic cells actively cross the blood/BM endothelium barrier to migrate into the BM compartment (**Figure 1**) [16]. This process is fairly rapid and occurs within hours and no longer than a day or two after stem cell infusion [16]. HSC homing is mediated in part by the binding of chemokine CXCR4 receptor on the surface of HSCs to their ligand, stromal cell-derived factor-1 (SDF-1) expressed by BM stromal cells [17]. Stem cell homing precedes engraftment, corresponding to proliferation and differentiation of hematopoietic stem cells (HSCs) to produce mature, functional hematopoietic cells within the BM [18]. One study claimed that only 18–20% of all intravenously transplanted stem cells, including different subsets, seeded in the BM, with UCB stem cell seeding even lower [19]. Another study demonstrated that human UCB stem cell seeding efficiency in NOD/SCID mice was found to be less than that for

Due to the curative potential of UCB transplantation, several approaches have been investigated to improve UCB stem cell homing to the BM. In one study inhibi-

human CB cells with

stem cell transplantation as well as allogeneic stem cell transplantation.

**2. Current methods to improve UCB HSPC homing**

tion of CD26 peptidase activity by pretreating purified CD34+

**152**

**Figure 1.**

BM (4.4% versus 20%) [20].

Diprotin A significantly enhanced engraftment of HSCs from human UCB into NOD/SCID mice [21]. A CD26 peptidase inhibitor, sitagliptin, was investigated in a clinical trial with encouraging results in engraftment of adults with hematological malignancies after using a single unit UCB transplant [22]. Another strategy taken involved direct intrabone administration of cord blood cells into the superiorposterior iliac crest under rapid general anesthesia. Though this strategy produced impressive results in one study [23], another study showed contradictory results [24]. Therefore this procedure has not been widely accepted. In exploring further defects in cord blood stem cell homing, it was found that cord blood CD34+ cells have reduced alpha(1,3)-fucosyltransferase (FucT) expression and activity causing a depletion of cord blood stem cell surface ligands necessary for interaction with adhesion molecules at time of stem cell homing [25]. Forcing fucosylation was found to be clinically feasible with encouraging engraftment efficiency data in the double UCB transplant setting [26]. Some of these interventions require significant logistical support, and some require graft manipulation; accordingly, there is an urgent need to identify safe and practical interventions to enhance UCB homing and engraftment for patients with hematologic malignancies who are undergoing allogeneic stem cell transplantation.
