**1. Introduction**

Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for severe hematological malignancies and other severe disorders of the blood, immune system, and bone marrow. Its usage has increased rapidly and substantially since the first HSCT in 1957, almost

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

60 years ago, and with the one millionth HSCT being performed in 2013 [1]. Over 40,000 HSCT were performed in Europe in 2014 for more than 36,000 individuals for all disease indications, with 58% being autologous and the remainder receiving HSCs sourced from related and unrelated allogeneic donors of bone marrow (BM), peripheral blood after induced mobilization (mPB) or umbilical cord blood (UCB) [2]. The main indications for these HSCTs were leukemias, lymphoid neoplasias, solid tumors, and nonmalignant diseases [2].

The year 2013 also marked the 25th anniversary of the first UCB HSCT in a child with Fanconi's anemia using an human leukocyte antigen (HLA)-identical sibling UCB donation [3]. The recipient remains alive and well, having achieved full donor chimaerism. Worldwide, there are estimated to be over 730,000 unrelated UCB units banked for public use in more than 160 international cord blood banks, and more than 35,000 have been transplanted [3, 4]. In 2014, UCB accounted for 2% of allogeneic HSCT in Europe, with substantially more in the USA and Japan [2]. From available worldwide data, the Center for International Blood and Bone Marrow Research (CIBMTR) reported that UCB accounted for 8% of allogeneic HSCTs [2–6]. In their international survey report of 2015, the CIBMTR recorded that 32% of pediatric and 10% of adult-unrelated donor HSCTs used UCB as the HSC source [6]. Indications for allogeneic UCB HSCT have included hematological malignancies, bone marrow failure, severe anemias, metabolic storage diseases, immune-deficiencies, and some cancers. Studies in December 2014 estimated that there were over 4 million UCB units banked for private/family use (see [4]) of which at least 1015 (530 autologous and 485 allogeneic) had been transplanted by December 2013 (see [4]). Indications for family UCB HSCTs have included the severe hemoglobinopathies and the treatment of brain injury (see [4]), and these and other indications will be discussed further.

UCB has several advantages over bone marrow or mobilized peripheral blood as the HSCT cell source. It is noninvasive, can be collected, tested, HLA- typed and banked ahead of use, is readily available for urgent HSCTs, and for black and minority ethnic recipients who do not have a matched bone marrow or peripheral blood donor, demonstrates less-associated graft versus host disease (GvHD) in the allogeneic setting, particularly where less rigorous HLA matching is possible and is not subject to donor attrition (reviewed in Refs. [7–10]). Its main disadvantages are its limited cell dose, delayed hematological engraftment (early neutrophil and platelet and long term immune reconstitution), lack of additional donor lymphocytes for infusion and interbank variability in viable hematopoietic stem and progenitor cell (HSPC) content on product release. It may also be subject to changing accreditation and quality control standards between the time of banking and its use, and the UCB donor may have immunological or hematopoietic disorders that are not manifested at the time of donation or during transplant follow-up (reviewed in Refs. [7–10]). UCB HSPC can also be used for other purposes. These include generating adequate supplies of mature blood cells from the HSPCs ex vivo for transfusion into difficult-to-transfuse patients or modulating resistance to specific acquired infections and correcting monogenic gene disorders, in dividing HSC, using new genome editing technologies [11–14].

A single UCB unit generally has sufficient HSCs for pediatric, but not adult HSCT [11–14]. Different approaches have been used to enhance the HSPC numbers in UCB grafts so that their use can be extended to adult HSCTs, to develop further uses for banked cord blood units in other transfusion and transplant therapies or as diagnostic or research reagents, or to improve their engraftment in the bone marrow hematopoietic stem cell niche. These include the use of double UCB units for transplant without or with ex vivo manipulation of cells to enhance their HSPC dose or improve engraftment. The readouts following the manipulation and expansion of HSPCs include assessing the levels of defined hematopoietic progenitor cell subsets using specific markers and using functional assays to demonstrate hematopoietic repopulation capacity in vivo in surrogate animal models (see Refs. [15, 16]). The majority of HSPCs in human UCB are found in the CD133+ and CD34+ fractions of CD45+ cells [17–27] and these progenitors can be further segregated into or enriched for HSC or their immediate myeloid and lymphoid progeny with the discriminatory marker sets identified by Notta et al. [15].

60 years ago, and with the one millionth HSCT being performed in 2013 [1]. Over 40,000 HSCT were performed in Europe in 2014 for more than 36,000 individuals for all disease indications, with 58% being autologous and the remainder receiving HSCs sourced from related and unrelated allogeneic donors of bone marrow (BM), peripheral blood after induced mobilization (mPB) or umbilical cord blood (UCB) [2]. The main indications for these HSCTs were leukemias,

The year 2013 also marked the 25th anniversary of the first UCB HSCT in a child with Fanconi's anemia using an human leukocyte antigen (HLA)-identical sibling UCB donation [3]. The recipient remains alive and well, having achieved full donor chimaerism. Worldwide, there are estimated to be over 730,000 unrelated UCB units banked for public use in more than 160 international cord blood banks, and more than 35,000 have been transplanted [3, 4]. In 2014, UCB accounted for 2% of allogeneic HSCT in Europe, with substantially more in the USA and Japan [2]. From available worldwide data, the Center for International Blood and Bone Marrow Research (CIBMTR) reported that UCB accounted for 8% of allogeneic HSCTs [2–6]. In their international survey report of 2015, the CIBMTR recorded that 32% of pediatric and 10% of adult-unrelated donor HSCTs used UCB as the HSC source [6]. Indications for allogeneic UCB HSCT have included hematological malignancies, bone marrow failure, severe anemias, metabolic storage diseases, immune-deficiencies, and some cancers. Studies in December 2014 estimated that there were over 4 million UCB units banked for private/family use (see [4]) of which at least 1015 (530 autologous and 485 allogeneic) had been transplanted by December 2013 (see [4]). Indications for family UCB HSCTs have included the severe hemoglobinopathies and the treatment of brain injury (see [4]), and these and other indications will be discussed

UCB has several advantages over bone marrow or mobilized peripheral blood as the HSCT cell source. It is noninvasive, can be collected, tested, HLA- typed and banked ahead of use, is readily available for urgent HSCTs, and for black and minority ethnic recipients who do not have a matched bone marrow or peripheral blood donor, demonstrates less-associated graft versus host disease (GvHD) in the allogeneic setting, particularly where less rigorous HLA matching is possible and is not subject to donor attrition (reviewed in Refs. [7–10]). Its main disadvantages are its limited cell dose, delayed hematological engraftment (early neutrophil and platelet and long term immune reconstitution), lack of additional donor lymphocytes for infusion and interbank variability in viable hematopoietic stem and progenitor cell (HSPC) content on product release. It may also be subject to changing accreditation and quality control standards between the time of banking and its use, and the UCB donor may have immunological or hematopoietic disorders that are not manifested at the time of donation or during transplant follow-up (reviewed in Refs. [7–10]). UCB HSPC can also be used for other purposes. These include generating adequate supplies of mature blood cells from the HSPCs ex vivo for transfusion into difficult-to-transfuse patients or modulating resistance to specific acquired infections and correcting monogenic gene disorders, in dividing HSC, using new genome

A single UCB unit generally has sufficient HSCs for pediatric, but not adult HSCT [11–14]. Different approaches have been used to enhance the HSPC numbers in UCB grafts so that their

lymphoid neoplasias, solid tumors, and nonmalignant diseases [2].

134 Umbilical Cord Blood Banking for Clinical Application and Regenerative Medicine

further.

editing technologies [11–14].

In this review, we will describe these lineage hierarchies in human UCB, the procedures used to expand or manipulate the engraftment of these HSPCs, and the established and potential clinical uses of both unmanipulated and ex vivo manipulated autologous and allogeneic UCB units.
