Open access peer-reviewed chapter

Umbilical Cord Blood and Cord Tissue Bank as a Source for Allogeneic Use

Written By

Tokiko Nagamura-Inoue and Fumitaka Nagamura

Submitted: October 27th, 2019 Reviewed: February 6th, 2020 Published: March 11th, 2020

DOI: 10.5772/intechopen.91649

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Abstract

Recently, umbilical cord blood (CB) has received attention as the allogeneic optimum source for immunotherapies. More recently, the umbilical cord (UC) has been rapidly utilized as an abundant source of mesenchymal stromal cells (MSCs), which migrate toward the inflammatory and damaged tissue to subside the inflammation and support tissue repair. Both CB and UC can be provided “off-the-shelf” cell products for immunotherapies and regenerative medicine. As biomedical wastes, CB and UC can be obtained noninvasively without any risks to the donor. CB cells and UC-derived MSCs (UC-MSCs) also have higher proliferation potentials than other cells obtained from adult tissues. In addition, UC-MSCs are less immunogenic and have significant immunosuppressive ability. Several clinical trials with CB or UC-MSCs have been conducted based on these advantages. The establishment of a stable supply system of CB and UC-MSCs is critical now for their utilization in regenerative and immune cell therapies. We have thus established the cord blood/cord bank, “IMSUT CORD,” as a new type of biobank, to supply both frozen CB and UC tissues and derived cells for research and clinical uses. In this chapter, we will introduce the overall flow from collection to shipment and discuss several issues that need to be resolved in unrelated allogeneic stable supply system.

Keywords

  • cord blood
  • umbilical cord
  • mesenchymal stromal cells
  • immune cell therapy
  • regenerative medicine
  • biobank
  • explant method
  • large-scale expansion

1. Introduction

Umbilical cord blood (CB) has been utilized as a source of hematopoietic stem cells for three decades. It could potentially also serve as the optimum source of immune cells, such as mononuclear cells (MNC), regulatory T cells, NK cells, and mesenchymal stromal cells (MSCs) with or without genetic modifications, for immunotherapy and neurogenic regeneration in some cases. In addition, UB could be prepared as readily available products [1].

It is well-known that human mesenchymal stromal cells (MSCs) can be harvested from various tissues that include the bone marrow (BM) [2], cord blood (CB) [3], adipose tissue [4], placenta [5], and umbilical cord (UC) [6]. Recently, clinical trials using MSCs for various diseases have been conducted, and some of them were approved. The BM is considered the traditional source of MSCs, and the characteristics and applications of BM-derived MSCs (BM-MSCs) have been studied in detail. However, the harvesting of these cells is associated with an invasive procedure, and it may cause hemorrhage, infection, and chronic pain. In addition, BM-MSCs exhibit accelerated senescence as the donors’ age [7].

On the other hand, both CB and UC are routinely discarded as medical waste. The harvesting of CB and UC-derived MSCs (UC-MSCs) is therefore noninvasive and painless. The CB drawn from the UC and placenta is well-known as the source of hematopoietic stem cells for CB transplantations. However, in this article, we focus on the CB as the source for immune cells and regenerative medicine, such as regulatory T cells (Treg), NK cells, MSCs, and so on. The UC is the conduit between the developing embryo and placenta and consists of two umbilical arteries and one umbilical vein buried in the Wharton’s jelly. UC-MSCs have the abilities of multipotency and self-renewal properties comparable or superior to MSCs derived from other tissues in some papers. For this reason, several private CB banks have begun to collect CB and UC. We have thus established the cord blood/cord bank, “IMSUT CORD”, as a new type of biobank, to supply both frozen UC tissues and master cells for research and clinical uses.

In this chapter, we will introduce the overall flow from collection to shipment as taking the example of IMSUT CORD and discuss several issues that need to be resolved in unrelated allogeneic off-the-shelf stable supply system at present.

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2. Cord blood and umbilical cord collection

There are many public and private CB banks in the world, in which procedures are nearly standardized intended for hematopoietic stem cell transplantation (HSCT) as shown in Section 5. The procedures include informed consent acquisition from the mother, collection of CB, processing, storage, to shipment, which have been already established. In the case of UC bank for unrelated allogeneic uses, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) which issued ICH Q5A as the regulation of materials for biological products requires the second blood test from the baby’s mother, to deny viral infection in window period at delivery. Figure 1 shows the overall process of banking in the mother’s side. We deal with both CB and UC. In the CB and UC collection hospitals, the purpose, overall process, private information policy, the right to withdrawal, 6-month health check, and second blood test for the mother to confirm the negative study of infection are explained to the mother, and she gives written consent as the guardian of the baby. In addition to obtaining informed consent, questionnaires about medical history, genetic history of the baby donor’s family, and history for the mother’s communicable disease risk behavior are conducted to survey their health. The CB and UC are then collected, and the mother’s blood is tested for infections. These documentations and tests in CB bank can be referred to UC banking as well, although additional safety tests for UC banking shall be required strictly. UC-MSCs from one donor can be delivered and administered to many patients. Especially when the CB and UC passed the safety and some quality tests at clinical grade, the mother is asked to receive the blood test to make sure that all infection tests are negative in 6 months after delivery. These second tests are demanded by the Pharmaceuticals and Medical Devised Agency (PMDA) like the FDA and EMA, because it should be proven that the donor’s mother and baby were not in the window period of viral infections at delivery. On the other hand, bacterial contamination is also taken care because the baby and placenta with UC come out from nonsterile vagina. We collect UC in the case of a scheduled cesarean section to reduce the possibility of contamination due to the exposure to the vaginal bacterial/fungal flora.

Figure 1.

Overall flow from informed consent acquisition to shipment.

CB and UC are then transported from the collection hospitals to the CB/UC bank under controlled and validated temperature. CB is transported at validated temperature range (2–25°C) to protect cell viability, and the UC is cooled at 2–10°C in our facility.

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3. Cord blood processing

Among the processing methods to obtain nucleated cells from CB for hematopoietic stem cell transplantation, the hydroxyethyl starch (HES) centrifugation method (HES method) is the most efficient and common. The HES method originated from the New York Blood Center CB bank [8]. Recently, automated CB processing SEPAX® (GE Healthcare Life Sciences) [9] and AutoXpress Platform® (Cesca Therapeutics, Inc.) [10] have been developed. For CB cryopreservation, DMSO and Dextran 40 together with CB-plasma are used worldwide [8].

On the other hand, no processing method of fresh or frozen CB not for hematopoietic stem cell transplantation has been settled as standard. The use of mononuclear cells (MNCs) obtained by the Ficoll-Paque centrifugation method (Ficoll method) or cell sorting with antibody-conjugated magnetic beads might be a new candidate for further processing and culture method. CB processed by HES method resulted in whole nucleated cells including neutrophils, monocytes, lymphocytes, and nucleated red blood cells with some amount of red blood cells (RBC). The recovery rate of hematopoietic stem cells and mononuclear cells processed by HES method is superior to those by Ficoll method. That is why HES method is introduced by CB banks in the world [8]. However, neutrophils in the nucleated cells and residual RBC may cause the aggregation resulting in the difficulty of further processing, when the frozen and thawed cells are diluted with large volume of isotonic solutions such as medium. Only frozen-thawed CB nucleated cells can be diluted with dextran and albumin/saline solution [8]. On the other hand, frozen-thawed MNCs processed by Ficoll method does not require such a special solution and can be diluted with medium and PBS, although the recovery rate of MNCs from the fresh CB by Ficoll method is less than that by HES methods.

MSCs derived from fresh CB are difficult to expand. Only one company, Medipost Co., Ltd., in Korea, has succeeded in expanding CB-derived MSCs. Their product, Cartistem®, has been approved by the Ministry of Food and Drug Safety in Korea for the treatment of osteoarthritis [11].

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4. Umbilical cord processing

There are diverse procedures and culture methods for the isolation of MSCs from the various compartments of UC, such as Wharton’s jelly, veins, arteries, UC lining membrane, subamnion, and perivascular regions [12]. The isolation methods of MSCs from the Wharton’s jelly, vein, and arteries of UC are reported previously, although the marked differences were not found as far as the 10% fetal bovine serum (FBS) and α minimum essential medium (MEM) [13]. There are several papers to obtain MSCs from whole UC versus Wharton’s jelly [14] or different parts of the same UC [15], but we suggest that to process from whole UC seems sufficient and simple for further processing [15]. Despite the wide range of isolation and culture procedures, the different groups seem to agree on the cryopreservation of UC tissue [16] and explant method [17] followed by the harvest of migrating cells from tissue. However, large-scale culture methods remain to be determined. Figure 2 shows the example of scheme of CB and UC collection and process and shipping to clinical use.

Figure 2.

IMSUT CORD scheme of CB and UC from collection to shipping for clinical use.

4.1 Cryopreservation of UC tissue

It is known that the UC tissue can be frozen in a cryoprotectant. This possibility of cryopreservation is the advantages of UC tissue for both clinical and research uses. The reasons of the advantages are:

  1. UC tissue processing can be started after the donor’s health and infection statuses are confirmed well. This leads to initial cost-effectiveness because unnecessary works using inappropriate materials are eliminated. In addition, we can thaw a small amount of the UC to survey, before culturing MSCs in a large scale.

  2. Storage of the tissues of origin allows us to keep traceability and to check the quality as the biological resources at a later date.

  3. When new reagents or techniques were developed in the future, we can isolate novel cells from the cryopreserved UC tissues.

  4. If the donor, the baby, has diseases that can be treated with autologous cells, including iPS cells or gene-modified cells, or autologous UC-MSCs, the cryopreserved UC tissues would be the appropriate source.

Several animal serum-free cryoprotectants containing 5–10% dimethyl sulfoxide (DMSO) are available. Whether the use of serum originating from animals, such as fetal bovine serum (FBS), is required, is critical, because it adds the risk of the transmission of zoonotic infections, immunological reactions, and additional regulatory issues [18]. There are several reports of cryopreservation of the UC tissue, using serum-free and xenogeneic animal-free (xeno-free) cryoprotectants. Ennis et al. introduced CryoStor CS10® (BioLife Solutions Inc., WA) for isolating human UC perivascular cells (HUPVCs). However, they did not show the comparative test results to those of fresh UC [19]. Roy et al. reported the cryopreservation of the UC tissue in 10% DMSO and 0.2 M sucrose solution, but the cumulative cell yield derived from the frozen-thawed UC-MSCs in their solution was inferior to that of fresh UC-MSCs [20]. We previously reported the cryopreservation of UC tissue, with no impact on viability, using a serum- and animal origin-free cryoprotectant, STEM-CELLBANKER® [16]. We demonstrated that cells derived from UC cryopreserved in this manner retained the phenotypic characteristics of MSCs, including the immunosuppressive activity in allogeneic mixed lymphocyte reactions, as well as differentiation potential. As shown in Figure 2, with the cryopreservation of UC tissue, UC processing might be altered.

4.2 Improved explant method

There are two major approaches after frozen-thawed UC tissue: explant and enzymatic digestion methods. Frozen-thawed UC tissue is manually minced into small fragments approximately 1–2 mm3 in size. Mincing is preferred to using a surgical scalpel or the use of an autologous mixer. These fragments are aligned and seeded regularly on a tissue culture-treated dish. After the tissue fragments attach to the bottom of the dish, culture media is added, slowly and gently in order not to detach the fragments [21, 22, 23, 24]. Media is then refreshed every 3–7 days for 2–4 weeks until the fibroblast-like adherent cells reach 80–90% confluence. Subsequently, adherent cells and tissue fragments are rinsed once with PBS, detached using trypsin, and washed with media. The culture is then filtered to remove tissue fragments. The disadvantage in the explant method is that tissue fragments often float in media, resulting in the poor recovery of cells. To protect the exfoliation of tissue fragments from the bottom of the culture dish, we introduced stainless steel mesh (Cellamigo®; Tsubakimoto Chain Co.) shown in Figure 2, No. 8. In this manner, we can plate source tissue more quickly and harvest more MSCs. In addition, the incubation time required to reach 80–90% confluence is reduced [17].

In the enzymatic digestion method, UC is minced into small pieces and immersed in the media containing enzymes such as collagenase, or a combination of collagenase and hyaluronidase with or without trypsin [21, 24, 25, 26]. The cells dissociated by the enzymes are then cultured until they reach full confluence. However, the digestion method is costly and time-consuming and may result in decreased cell viability due to lytic activity and varying sensitivity of the cells to collagenase. In addition, the initial harvested cells include more of the other types of cells compared with that harvested using the explant method.

4.3 Large-scale expansion and harvesting the cells

It is critical to consider how much we can expand the UC-MSCs to allow allogeneic “off-the-shelf” industrial availability, because the proliferation of adherent cells needs a large surface area. The conventional method uses multilayered flasks, and the cells are cultured in incubators installed in cleanrooms. These multilayer flasks can consistently support the expansion of UC-MSCs, and the state of cell confluence can be examined under the microscope. However, this method requires the considerable involvement of operators because the processes of seeding, refreshment, passage, and harvest require individual and manual works. Several companies have introduced the spinner bioreactor with a microcarrier made of plastic, dextran, denatured collagen-coated beads, and other components. The bioreactor system may reduce the number of operators required and may allow to reduce the clean levels of facility since it is a closed system. On the contrary, several critical problems of the bioreactor system exist. The cost of equipment is high and it is difficult to evaluate cell proliferation environment such as pH, lactate, and so on. When some microcarriers are torn off by spinner, or undigested microcarriers are residual in the final products, we have no ideas to remove the residual microcarriers completely. Recently, a plastic bag bioreactor system with a microcarrier in gentle locking was reported [27]. The most critical problem is that the cells produced by the flask-based culture method may be different from those by bioreactors. Harvesting cells on a large scale is still not easy. Recently, filter-based cell concentration and washing systems were introduced (https://www.kaneka.co.jp/en/business/healthcare/med_006.html, KANEKA, Japan). Automatic cell packaging may be also required in large-scale expansion.

The academic culture level such as IMSUT CORD is at small to middle scale. Only the company may have the ability to expand the cells at extra-large scale and maintain to control and supply the cell product for clinic constantly.

4.4 Long-term cryopreservation

Master and product cells of UC-MSCs for clinical use are usually required for long-term cryopreservation, together with records on the donor infant and the mother. There are several cryoprotectants for long-term cryopreservation. The most popular cryoprotectant consists of 5–10% dimethyl sulfoxide with human albumin. Recently, serum-free cryoprotectants, described in Section 4.1, have been commercialized and are thought to be more ideal compared to those containing human-derived serum. In addition to cryoprotectants, it is important to build an adequate record preservation system. Those who manage the long-term cryopreservation should preserve the records that include the documentation relating to the collection including donors, processing, results of quality tests, and instruments directly related to the products. The kinds of records and the length to be preserved are in accordance with the bank policies and standards and the corresponding domestic laws and regulations. It is necessary to discuss how long we should or we can cryopreserve CB and UC tissue, UC master cells, and product cells, in the technical and ethical aspects. In the technical aspect, the cell-preserving vessel to accommodate the cell suspension for long-term freezing should be durable in a liquid nitrogen. In the ethical aspect, we do not expect whether the babies can recapture their ownership of CB and UC even though their mother waived the ownership of them, when they grow up to be adult.

4.5 Quality and safety assurance of UC-MSCs

The Mesenchymal and Tissue Stem Cell Committee of the International Society for Cellular Therapy proposed the minimal criteria for defining human MSCs [2829]. First, MSCs must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73, and CD90 but not CD45, CD34, CD14 or CD11b, CD79α or CD19, and HLA-DR surface molecules. Third, MSCs must differentiate into adipocytes, chondroblasts, and osteoblasts in vitro [30, 31, 32]. Immunosuppressive effects have now become the most popular property of MSCs for potential clinical use [12]. Defect in HLA-class II expression with negative CD80 and CD86in UC-MSCs even in the presence of inflammatory cytokines such as IFN-γ can theoretically rescue them from immune recognition by CD4+ T cells [33]. MSCs can also inhibit proliferation of and cytokine secretion by immune cells, as well as alter subtypes of macrophage from M1 to M2 in vitro [34, 35, 36, 37]. This immunomodulation is linked mainly to soluble factors such as indoleamine 2,3-dioxygenase (IDO), PGE2, and HLA-G5 [38], hepatocyte growth factor, and transforming growth factor-β1 released from MSCs [39]. Further quality tests are dependent on clinical applications and characteristics of MSCs.

The safety tests required differ according to the risks of clinical applications. For example, the tests of CB banking for hematopoietic stem cell transplantation are different from those of UC-MSCs. Donor-recipient relation of the former is one-to-one, and the risk is limited to one patient. On the other hand, that relationship of the latter, as UC-MSCs master cells and product cells, is one-to-many, so hundreds of patients may suffer health injuries by one donor. Thus, the vials of UC-MSCs are tested thoroughly at a designated time not only known viruses but also unknown viruses. Those tests should follow the local, national or international applicable laws and regulations. More precise safety tests for CB and UC shall be described elsewhere for the respective products for clinical application.

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5. Standards and guidance for CB and UC from collection to release

There are international standards/guidance for CB collection, banking, and release of hematopoietic stem cell transplantation, such as the Foundation for the Accreditation of Cellular Therapy (FACT)/NETCORD [40], American association of Blood Banks (AABB), US Food and Drug Administration (FDA) shown in Table 1, and local standards or regulations under the applicable laws in respective countries. A CB/UC bank, facility, or individual should implement if the standard of practice in the community or applicable law establish additional requirements. International standards/guidance for biobanking process for UC collection, processing, culture, and release has not been settled, but collection and banking protocols can follow the CB banking standards and good tissue practice. Each CB/UC bank, facility, and individual should analyze its practices and procedures to determine whether additional standards apply. Compliance with the standards is not an exclusive means of complying with the standard of care in the industry or community or with local, national, or international laws or regulations [40]. Allogeneic public CB banks requested US FDA accreditation with FACT/NETCORD or AABB in the USA, while the CB banks in Europe (EU) required FACT/NetCord with additional requirements like FACT/JACIE standards, when it is requested by the respective national regulation affairs. There are many private or private-public combined CB banks in the world, which tend to follow the AABB standards and have the inspection and accreditation (http://www.aabb.org/sa/facilities/celltherapy/Documents/AABB-Accredited-Cord-Blood-Facilities.pdf).

Items Accreditation organization Standards or guidance titles
Cord blood (CB) processing for hematopoietic stem cell transplantation FACT/NETCORD
FACT/JACIE
International Standards for Cord Blood Collection, Banking, and Release for Administration
International Standards for Hematopoietic Cellular Therapy Product Collection, Processing, and Administration
http://www.factwebsite.org/cbstandards/
FDA in the USA Guidance for Industry: Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic Reconstitution for Specified Indications
Guidance for Industry and FDA Staff: Investigational New Drug Applications for Minimally Manipulated, Unrelated Allogeneic Placental/Umbilical Cord Blood Intended for Hematopoietic and Immunologic Reconstitution in Patients with Disorders Affecting the Hematopoietic System
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
AABB Standards for Cellular Therapy Services
http://www.aabb.org/sa/Pages/Standards-Portal.aspx
Umbilical cord-derived cells including mesenchymal stromal cells (UC-MSCs)/somatic cell or other derivative cells
CB not intended for hematopoietic stem cell transplantation
FACT Common standards for Cellular Therapies
http://www.factwebsite.org/cbstandards/
FDA in the USA Good Tissue Practice 21CFR 1271.210
Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)
Guidance for Industry: Preclinical Assessment of Investigational Cellular and Gene Therapy Products
Guidance for FDA Reviewers and Sponsors
Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs)
http://www.fda.gov/cber/guidelines.htm
AABB Standards for Cellular Therapy Services
http://www.aabb.org/sa/Pages/Standards-Portal.aspx
EMA in EU Tissues and Cells Directives: Guideline on human cell-based medicinal products (EMEA/CHMP/410896/2006) for ATMP
PMDA (Japan) Good Gene, Cellular, and Tissue-based Products Manufacturing Practice (GCTP)
Quality management system ISO ISO9001
ISO/TC276 (Draft)
https://www.iso.org/standard/62085.html

Table 1.

Standards or guidance related to cord blood and umbilical cord-derived cells.

Foundation for the Accreditation of Cellular Therapy, FACT; US Food and Drug Administration, FDA; American Association of Blood Banks, AABB; advanced therapy medicinal products, Pharmaceutical and medical devices agency (PMDA). This table does not include the law defined in each country. These standards, guidance, guidelines, and practices are not intended to apply all cell therapies using CB and UC. The CB/UC bank carefully chooses and implements them for your intended products under the applicable law.

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6. Special issues of CB and UC bank system for allogeneic use

The number of clinical trials using CB and UC-MSCs in the fields of immune cell therapies and regenerative medicine has been increasing. On the other hand, CB as a source of hematopoietic stem cell transplantation is less used recently, because the cell number is limited, the engraftment of HSC is delayed, and HLA haplo-identical HSCT is induced and controlled. These clinical trials are aimed uses that include severe acute graft-versus-host disease (GVHD) treatment, rapid engraftment of HSCT, and the prevention of severe acute GVHD. Clinical trials using CB- and UC-MSCs are summarized in Tables 2 and 3, respectively. We started a sponsor-investigator clinical trial using UC-derived MSCs for patients with treatment-resistant severe acute GVHD supported by the research fund of the Japan Agency for Medical Research and Development (AMED). Consistent supply is the critical key to conduct clinical trials and for marketing. For the stable supply of frozen CB and UC, or UC-derived MSCs, we have established a CB and UC bank, named IMSUT CORD, in our institute. This bank also provides CB and UC-MSCs for immunotherapy and regenerative medicine products to hospitals and pharmaceutical companies shown in Figure 2. The bank also provides frozen CB, frozen UC, master cells, and the cells after master cells as an intermediate products requiring further processing or more culture in the companies.

Authors Cell type Disease Patients number Age (range) year Route and procedure of administration Cell number/kg or body Results Adverse events
Brunstein et al. [41] CB-NC-derived Treg (CB from The New York Blood Center) Grade II–IV acute GVHD Treg: 11 61 (45–68) IV 3–100 × 106 Treg/kg aGVHD: Treg group 9%, control 45% cGVHD: Treg 0%, control 14% No dose-limiting infusion adverse events
Control: 22 60 (34–69)
Kellner et al. [42] Fucosylated or non-fucosylated UCB-Tregs HSCT 5 IV (−1 day of HSCT) 1 × 106/kg No infusion reactions
Zhu et al. [43] CB-MNC Chronic complete spinal cord injury 8 in Hong Kong 42.6 ± 2.7 IT (dorsal entry zone) 1.6–3.2 × 106 Walk 10 m, 15/20 pts. (p = 0.001), no necessity of assistance for bladder management, 12/20 (p = 0.001) and bowel management (p = 0.002) 1 neuropathic pain;1 subarachnoid hematoma and pneumocephalus due to cerebrospinal loss;1 arachnoid hemorrhage I HK group,
Phase I–II 20 in Kunming 36.9 ± 2.4 68 AEs including postoperative wound swelling; 9 pain
Overall 5 severe AE in 28 patients
Shah et al. [44] CB-MNC-derived NK cells (CB from MD Anderson Cord Blood Bank) Multiple myeloma undergoing autologous PBSCT 12 48–70 5 × 106, 1 × 107, 5 × 107 and 1 × 108 CB-NK cells/kg 10 achieved VGPR (8 near CR) as the best response No infusional toxicities and no GVHD
Lv et al. [45] CB-MSC + UC-MSCs Autism 14 CB-MNC9 CB-MNC and UC-MSCs14 no cells therapy CB-MNC: 7.08 (3.29–12.01) CB-MNC + UC-MSCs: 6.51 (3.98–9.83)Control: 5.02 (3.51–10.02) IV Proximately 2 × 106/kg CB-MNCs1 × 106/kg of UC-MSCs
4 times in 5–7 day
Improvement of CARS, ABC scores, and CGI evaluation at 24 weeks in CB-MNCs with UC-MSCs No treatment-related and no severe adverse effects
Dolstra et al. [46] CB-CD34-derived NK cells (CB from Cord Blood Bank Nijmegen) AML in old patients 10 68–76 IV 3 and 30 × 106/kg NK cell maturation in vivo, MRD become negative in 2/4 with MRD before IV No GVHD, no toxicity
Park et al. [47] CB-derived MSCs Rheumatoid arthritis 9 57.4 ± 10.0 IV 2.5 × 107, 5 × 107, or 1 × 108 DAS2/-ESR decreased, inflammatory cytokine levels are reduced No DLT, no major toxicity
Laskowitz et al. [48] CB-NC (CB from Carolinas Cord Blood Bank or MD Anderson Cord Blood Bank) Cerebral stroke 10 65.5 (45–79) IV on 3–9 days poststroke Cell dose 1.54 (0.84–3.34) × 107/kg, CD34+ 2.03 (0.10–6.80) × 105/kg All improved by at least one grade in Modified Rankin Score AE tolerated no serious AE
Huang et al. [49] CB-MSCs Cerebral palsy (age: 3–12) 27 (CB-MSCs) CB-MSCs: 7 (3–12) IV 27:4 CB-MSCs IV at 5 × 107 with basic rehabilitation treatment Significant improved of GMFM-88 evaluation No serious AE
27 (control) Control: 7 (3–12)
Kim et al. [50] CB-MSCs Moderate-to-severe atopic dermatitis 34 (7 in phase I, 27 in phase IIa) 29.07 ± 2.03 (n = 14) SC 2.5 × 107 Improved atopic dermatitis scores, pruritus score, serum IgE and eosinophil number No serious AE
28.08 ± 1.07 (n = 11) 5.0 × 107

Table 2.

Clinical trials using allogeneic cord blood.

AE, adverse event; AML, acute myeloid leukemia; CB, cord blood; UC, umbilical cord; MSCs, mesenchymal stromal cells; MNCs, mononuclear cells; NK cells, natural killer cells; Treg, regulatory T cells; GVHD, graft-versus-host disease; PBSCT, peripheral blood stem cell transplantation; IV, intravenous injection; SC, subcutaneous injection.

Authors Disease Patients number Age (range) year Route and procedure of administration Cell number/kg or body Frequency interval Results Adverse events
Engraftment facilitation and graft-versus-host disease (GVHD) in hematopoietic stem cell transplantation
Wu et al. [51] Severe steroid-resistant aGVHD 2 Pt 1:4 IV Pt 1: 3.3, 7.2, 8.0 × 106/kg 3 Improved No
Pt 2:6 IV Pt 2: 4.1 × 106/kg 1
Si et al. [52] Severe aplastic anemia 37 5 IV (7–10 days after HSCT) 1 × 106/kg 1 aGVHD II–IV; 17 of 37 (45.9%) No
(0.75–11.58) cGVHD, 7 of 37 (18.9%)
Wu et al. [53] Refractory/relapsed hematologic malignancy 50 26 (9–58) IV (4 h before haploidentical HSCT) 5 × 105/kg 1 aGVHD II–IV, 12 of 50 (24.0%) cGVHD, 17 of 45 (37.7%) (3 extended) No
Wu et al. [54] Severe AA 21 18 (4–31) IV (4 h before HSCT) 5 × 105/kg 1 aGVHD II-IV;12 of 21 (57.1%) 3 of 9 extended cGVHD No
Fu et al. [55] Refractory severe AA 5 15.2 (9–22) IV (2 days after PBSCT) 1 × 106/kg 1 No severe aGVHD or cGVHD No
Gao et al. [56] Prophylaxis of chronic GVHD after HLA-haploidentical stem cell transplantation 62 Age < 8, 15 pts.; 18–40, 39; >40, 8 IV 3 × 107 cells Until cGVHD occurred, leukemia relapsed, or 4 cycles cGVHD at 2 yr.: MSCs group 27.4%, control 49.0% (P = .021). Severe lung cGVHD: MSCs group 0, control 7 (P = .047) No
Zhu et al. [57] High-risk acute leukemia 25 11.2 (4–17) IV (before haploidentical HSCT) Median 1.14 × 106/kg (1.03–1.39 × 106/kg) 4 (over 7 days intervals) aGVHDI, 8 of 25 (32.0%) cytomegalovirus viremia, 23 of 25 (92.0%) No
Pan et al. [58] Extensive bone marrow necrosis of a chronic myeloid leukemia patient 1 10 iBM iBM: 2 × 107/kg 1 BM recovered No
IV IV: 2 pp. × 106/kg
Neurogenic injuries
Wang et al. [59] Traumatic brain injury 20 27.5 (5–48) Intrathecal (IT) 1 × 107 4 (5–7 days intervals) Motor functional recovery after 6 months No
Jin et al. [60] Hereditary spinocerebellar ataxia 16 39.9 (21–56) IV + intrathecal IV; 4 × 107 4 (over 7 days interval) Motor functional recovery after 6 months No
IT; 2 × 107 cells
Wang et al. [61] Cerebral palsy 16 (8 twins) 6.29 (3–12) IT 1–1.5 × 107 cells 4 (3–5 days intervals) Motor functional recovery after 1 and 6 months No
Diabetes mellitus
Guan et al. [62] DM (type 2) 6 40.5 (27–51) IV 1 × 106/kg 2 (2 weeks interval) Insulin-independent for 25–43 Mo, 3 dose reduction of insulin, others No
Hu et al. [63] DM (type 1) 15 17.6 IV 2.6 ± 1.2 × 107/kg 2 (4 weeks interval) HbA1c and C-peptide improvement in MSCs group No
Cai et al. [64] DM (type 1) 21 18–29 (5–28) at onset Supraselective pancreatic artery cannulation 1.1 × 106/kg, with autologous BM-MNC 1 Moderate improvement of metabolic measures 1 transient abdominal pain
Kong et al. [65] DM (type 2) 18 IV 1 × 106/kg Day 0 and until Day 90 if effective FBS reduced plasma C-peptide and regulatory T cells increased 4/18: slight fever
Heart and angioplasty
Cai et al. [66] Avascular necrosis of the femoral head 30 41.6 (19–63) Femoral head artery (co transplant with autologous BM) Autologous BM-BM-MNCs, 60.7 ± 11.5 × 106/kg
UC-MSCs, 1 × 106/kg
1 Improved No
Can et al. [67] Myocardial ischemia 39 30–80 Intracoronary 2 × 107/kg 1 Ongoing No
Zhao et al. [68] Severe systolic heart failure 30 52.9 (20–79) Intracoronary Unknown 1 Cardiac remodeling and function improved with reduced mortality rate No
Li et al. [69] Coronary chronic total occlusion 15 Unknown Intracoronary 3 × 106/4 × 106/5 × 106/kg 1 Infarcted size reduced with improved left ventricular EF No
Musialek et al. [70] Acute myocardial infarction 10 55.6 (32–65) Intracoronary 3 × 107/body 1 Feasible and procedural safe as off-the-shelf cellular therapy Transient fever (38.9°C)
Bartolucci [71] Heart failure 15 57.33 ± 10.05 IV 1 × 106 cells/kg 1 Significant improvements in LVEF, NYHA functional class, Minnesota Living with Heart Failure Questionnaire No
Liver
Xue et al. [72] Decompensated liver cirrhosis 50 Unknown Intrahepatic artery 3 × 107/body 1 Increase of serum albumin No
Wang et al. [73] Primary biliary cirrhosis 7 49 (33–58) IV 5 × 105/kg at 4 weeks interval 3 ALP and γ-GTP No
Shi et al. [74] Prevention of acute liver allograft rejection 14 (13, single dose, 1 multiple dose) 57 ± 12 IV 1 × 106 cells Single (13 pts), 3 times every 4w (1 pt) Decreases of ALT, AST, T-BIL Histologic improvements, MSCs 6, control 0. No
Liang et al. [75] Liver cirrhosis caused by autoimmune diseases 23 (2 CB-MSC, 1 BM MSC) 53.4 (35–70) IV 1 × 106 cells/kg 1 Not statistically significant improvement 2, fever; 3, mild fidgetiness, suffered from insomnia
Zhang et al. [76] Ischemic-type biliary lesions following liver transplantation 12 47.3 ± 10.1 IV 1 × 106 cells/kg 6 (1, 2, 4, 8, 12, 16 weeks) Significantly decreased need for interventional therapies. 1-, 2-yr graft survival rates: MSCs group (100%, 83.3%), control group (72.9%, 68.6%) No
Xu et al. [77] Hepatitis B virus-related acute-on-chronic liver failure 30:UC-MSC UC-MSC: 40.67 ± 9.89 IV 105 cells/kg UC-MSC, once a week, 4 times No significant improvement of short-term prognosis Fever, UC-MSC 11 pts., PE + UC-MSC 6 pts
20, UC-MSC + plasma exchange UC-MSC/plasma exchange, 42.00 ± 6.55 IV UC-MSC/PE: first 2 UC-MSC: 2nd day after 1st, 3rd PE treatments
Gastrointestinal tract
Zhang et al. [78] Crohn’s disease 41 32.7 (20–41) IV 1 × 106 cells/kg Once a week, four times Decreases of CDAI, HBI, corticosteroid dosage Fever 4, upper respiratory tract infection, 7
Hu et al. [79] Ulcerative colitis 34 42.9 ± 23.1 IV then IA 0.5 × 106 cells/kg 2, 7 days Decreases of median Mayo score, histology score. Improvement of IBDQ scores No
Skin
Hashemi et al. [80] Chronic skin ulcer 5 30–60 Covered by acellular amniotic membrane seeded with WJSCs About 2 × 106 cells were seeded Epithelial surface of acellular amniotic membrane Significantly decreased wound healing time, wound size. Significantly declined wound size after 6, 9 days Not stated
Kidney
Sun et al. [81] Prevention of delayed graft function and acute rejection in renal transplantation 21 41.0 ± 11.5 IV 2 × 106 cells/kg (before transplantation), 5 × 106 (during surgery) No significant improvement No
Deng et al. [82] Lupus nephritis 12 MSC, 6 placebo 29 ± 10 IV 1 × 108 cells 2 times 1 wk. interval Not statistically significant improvement 1: leucopenia, pneumonia, subcutaneous abscess, 1: severe pneumonia
Autoimmune diseases
Wang et al. [83] Active and refractory SLE 40 17–54 IV 1 × 106 cells/kg on day 0 and 7 2 MCR (13 of 40, 32.5%), PCR (11 of 40, 27.5%) during 12 months, although several patients relapse after 6 months No
Wang et al. [84] RA 136 46.1 IV 4 × 107 cells, 2nd in 3 months later 1 (n = 112) Decreases of serum TNF-α, IL-6, increase of regulatory T cells. Significant remission for 3–6 months Mild fever (<38.5°C) without treatment at injection, 6 patients
2 (n = 24)
Riordan et al. [85] Multiple sclerosis 20 41.2 (24–55) IV 2 × 107 UC-MSC 7 (1–4 days) Significant improvements of various symptoms. Inactive lesions by MRI in 15/18 patients. (83.3%) after 1 year Headache, fatigue
Others
He et al. [86] Severe sepsis 15 (3 cohorts) 56 (25–72) IV 1 × 106 cells/kg 1 System clinical outcomes are not changed No
2 × 106 cells/kg
3 × 106 cells/kg
Cao et al. [87] Recurrent intrauterine adhesions 27 35.1 ± 3.8 (27–42) Loaded onto a collagen scaffold 1 × 107 1 Pregnant, 10 of 26 patients No

Table 3.

Clinical trials using allogeneic umbilical cord-derived mesenchymal stromal cells.

aGVHD, acute graft-versus-host disease; cGVHD, chronic GVHD; HSCT, hematopoietic stem cell transplantation; AA, aplastic anemia; BM, bone marrow; IT, intrathecal injection; AE, adverse event; AML, acute myeloid leukemia; CB, cord blood; UC, umbilical cord; BM, bone marrow; PE, plasma exchange; RA, rheumatoid arthritis; MSCs, mesenchymal stromal cells; DM, diabetes mellitus; FBS, fast blood sugar; ES, ejection fraction; IV, intravenous injection; SC, subcutaneous injection; DM, diabetes mellitus.

The following are also the major points for managing CB and UC banking.

First, to build an adequate quality management system to serve the resource of cell therapy products, we have introduced the concept of the ISO 9001 and obtained its certification, and as a result, we introduced the concept of PDCA cycle. Second, involvements of various kinds of specialists must be considered. There are many procedures, such as collection, obtaining informed consent, application to ethics review committee, and document management. Third, health check and infection test of the donor’s mother are required to ensure that no infection is detected after window period of infections. In this process, both traceability and personal information protection must be satisfied. Fourth, we respect the right of decision to donate, rejection, or withdrawal. Donor’s mother should be explained the policy of the bank that the consented withdrawal time is set at the initiation of processing for clinical use. Although the CB and UC belong to the baby, we obtain informed consent from the donor’s mother as guardianship and ownership are asked to be transferred to the bank. Fifth, there is also the issue of how long the UC tissue and UC-MSCs can be cryopreserved. For example, in the Japanese public CB bank for HSCT, the CB is cryopreserved for 10 years as a clinical grade of HSC source. After this period, they are used for basic research or preclinical studies or discarded if they are not used for research. A cryopreservation period of 10 years for UC and UC-MSCs may be the first threshold to be checked. In addition, we disclose the information in website for the mothers who have not been explained about the new researches or new clinical trials at the first IC acquisition. Lastly, because unlike CB, the UC is a tissue considered as a part of the perinatal appendage, we must follow the tissue transport and medical disposal/waste regulations under the applicable laws or local rules and ethical standards.

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7. Private CB and UC banking for autologous and family use

Recently, there are an increasing number of private CB banks, which have initiated to serve the cryopreservation of UC, i.e., private CB and UC bank. Using private autologous CB, clinical trials for cerebral palsy caused by hypoxic ischemic encephalopathy (HIE) reported their efficacy [88], although the collection of CB is difficult for the baby in such a severe situation of delivery, resulting in the limited application entry. Recently, we obtained the proof of concept that the UC-MSCs attenuated the neurogenic and functional damage caused by intraventricular hemorrhage (IVH) in newborn model mice. Duke University implemented the clinical trial using allogeneic UC tissue-derived cells for the patients with HIE. Allogeneic off-the-shelf UC-MSCs are a promising source; however, we do not know the adverse events such as HLA antibody induction caused by long-term repeated injections of allogeneic cells. Therefore, autologous use of CB and UC is still challenged to be discussed continuously.

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8. Conclusion

Although several problems still remain to be dissolved, operation of adequate CB and UC bank should be considered as the provider of cell source for regenerative and immune cell therapy, because of their prominent characteristics and convenient and noninvasive collection.

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Acknowledgments

This study was supported by Grants-in-Aids for Scientific Research from the Japan Agency for Medical Research and Development (AMED) (19be0504001h0002). We thank Kamisato A. PhD. for ethical support. We specially thank Takahashi A. MT, Ms. Hori A., Yamamoto Y. MT., Mr. Miharu Y. MT, Ms. Izawa, and MS. Nagaya N., for processing and quality management. We also thank the staff of NTT Medical Center Hospital and Yamaguchi Hospital, Tokyo, for their assistance with the collection of UC and CB.

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Written By

Tokiko Nagamura-Inoue and Fumitaka Nagamura

Submitted: October 27th, 2019 Reviewed: February 6th, 2020 Published: March 11th, 2020