Numerous publications have described the regenerative ability of cord blood cells in a myriad of preclinical disease models. Although the purpose of this paper is to discuss the immunology of cord blood transplants for regenerative uses, we will first overview some of the therapeutic stem cell populations found in cord blood so that we may discuss their immunogenic consequences later in the paper.
Hematopoietic stem cells
The original clinically attractive feature of cord blood was the high concentration of hematopoietic stem cells, which is similar to that found in bone marrow: approximately 0.1–0.8 CD34+ cells per 100 nucleated cells. However, in contrast to marrow, CD34+ cells from cord blood possess higher proliferative potential in vitro [15], superior numbers of long term culture initiating cells and SCID repopulating cells [16,17], as well as higher telomerase activity [18]. The potent hematopoietic activity of cord blood derived CD34+ cells may be attributed to the fact that cord blood is a much more developmentally immature source of stem cells as opposed to stem cells derived from adult sources. Attesting to the robust hematopoietic activity of cord blood derived CD34+ cells in comparison to bone marrow cells is the fact that successful reconstitution, albeit delayed, of post-ablative hematopoiesis occurs in patients receiving approximately one tenth of the total nucleated cell number in a cord blood graft compared to a bone marrow graft.
Endothelial progenitors and angiogenesis stimulating cells
In addition to being a source of hematopoietic cells, cord blood contains potent angiogenesis stimulating cells. Several phenotypes have been ascribed to cord blood angiogenic stimulating cells. In one report, the CD34+, CD11b+ fraction, which is approximately less than half of the CD34+ fraction of cord blood was demonstrated to possess ability to differentiate into functional endothelial cells in vitro and in vivo [19]. In another report, VEGF-R3+, CD34+ cells were shown to possess not only the ability to differentiate into endothelial cells in vivo, but also to be able to expand approximately 40-fold in vitro and subsequently maintain angiogenic function in vivo. The same study demonstrated that the concentration of this endothelial progenitor fraction found in cord blood CD34+ cells is approximately tenfold higher as compared to bone marrow CD34+ cells [20]. Regardless of the phenotype of the cord blood cell with angiogenesis stimulating ability, unfractionated cord blood mononuclear cells have also been used in numerous animal models [21-23], as well as in the clinic [9], for successful stimulation of angiogenesis.
In addition to endothelial progenitors, mesenchymal stem cells (discussed below in more detail), which are found in cord blood, are known to secrete numerous cytokines and growth factors such as VEGF and FGF-2 [24,25] which stimulate angiogenic processes. In fact, there are reports of mesenchymal stem cells contributing to angiogenesis through direct differentiation into endothelial cells [26].
Mesenchymal stem cells
Mesenchymal stem cells are a type of cell capable of differentiating into various non-hematopoietic tissues. Currently this cell population is second to bone marrow stem cells in terms of clinical entry in that Phase III clinical trials are already underway with these cells. Mesenchymal stem cells are classically defined as adhere to plastic and expressing a non-hematopoietic cell surface phenotype, consisting of CD34-, CD45-, HLA-DR-, while possessing markers such as STRO-1, VCAM, CD13, CD29, CD44, CD90, CD105, SH-3, and STRO-1 [27]. To date mesenchymal stem cells have been purified from bone marrow [28], adipose tissue [29], placenta [30,31], scalp tissue [32] and cord blood [33]. Cord blood-derived mesenchymal stem cells have demonstrated ability to differentiate into a wide variety of tissues in vitro including neuronal [34-36], hepatic [37,38], osteoblastic [39], and cardiac [33]. An important aspect of this cell population is their anti-inflammatory and immunomodulator activity. For example, they constitutively secrete immune inhibitory cytokines such as IL-10 and TGF-β while maintaining ability to present antigens to T cells, thus suggesting they may act as a tolerogenic antigen presenting cell [40,41]. Conceptually, the mesenchymal content of umbilical cord blood grafts may explain the tolerogenic capabilities, which some have speculated to be donor specific.
Although the majority of published studies have examined bone marrow derived mesenchymal stem cells, and thus are outside the scope of the present review, it is important to note differences between mesenchymal stem cells derived from different sources. A recent study compared mesenchymal stem cells from bone marrow, cord blood and adipose. Cord blood mesenchymal stem cells which were capable of expansion to approximately 20 times, whereas adipose derived cells expanded an average of 8 times and bone marrow derived cells expanded 5 times [42]. This, and other studies support the important role of mesenchymal stem cell content in the biological activities of the cord blood graft.
Unrestricted somatic stem cells
Cells with markers and activities resembling embryonic stem cells have been found in cord blood. Zhao et al identified a population of CD34- cells expressing OCT-4, Nanog, SSEA-3 and SSEA-4, which could differentiate into cells of the mesoderm, ectoderm and endoderm lineage. In vivo administration of these cells into the streptozotocin-induced murine model of diabetes was able to significantly reduce hypoglycemia [43]. The existence of cells with such pluripotency in cord blood was also observed by Kogler et al who identified an Unrestricted Somatic Stem Cell (USSC) with capability of differentiation into functional osteoblasts, chondroblasts, adipocytes, hematopoietic and neural cells. USSC were demonstrated to be capable of > 40 population doublings in vitro without spontaneous differentiation or loss of telomere length. Interestingly, administration of these cells (derived from human cord blood) into fetal sheep resulted significant human hematopoiesis (up to 5%), hepatic chimerism with > 20% albumin-producing human parenchymal hepatic cells, as well as detection of human cardiomyocytes. The mechanism of differentiation was not associated with fusion [44]. Support for presence of such pluripotency in cord blood cells also comes from a similar experiment in which CD34+ Lineage- cells were transfected with GFP and administered in utero to goats. GFP+ cells were detected in blood, bone marrow, spleen, liver, kidney, muscle, lung, and heart of the recipient goats (1.2–36% of all cells examined) [45]. In other studies, McGuckin et al demonstrated that culture of cord blood cells that have been depleted of lineage committed cells in a TPO, c-kit, and flt-3 ligand culture express markers of embryonic stem cells including TRA-1–60, TRA-1–81, SSEA-4, SSEA-3 and Oct-4. Functionally, these cells also demonstrated pluripotent differentiation ability and in vivo hematopoietic activity [46-48].
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