Repurposing the Cord Blood Bank for Haplobanking of HLA-Homozygous iPSCs and Their Usefulness to Multiple Populations

Abstract

Although autologous induced pluripotent stem cells (iPSCs) can potentially be useful for treating patients without immune rejection, in reality it will be extremely expensive and labor-intensive to make iPSCs to realize personalized medicine. An alternative approach is to make use of human leukocyte antigen (HLA) haplotype homozygous donors to provide HLA matched iPSC products to significant numbers of patients. To establish a haplobank of iPSCs, we repurposed the cord blood bank by screening ∼4,200 high resolution HLA typed cord blood samples, and selected those homozygous for the 10 most frequent HLA-A,-B,-DRB1 haplotypes in the Korean population. Following the generation of 10 iPSC lines, we conducted a comprehensive characterization, including morphology, expression of pluripotent markers and cell surface antigens, three-germ layer formation, vector clearance, mycoplasma/microbiological/viral contamination, endotoxin, and short tandem repeat (STR) assays. Various genomic analyses using microarray and comparative genomic hybridization (aCGH)-based single nucleotide polymorphism (SNP) and copy number variation (CNV) were also conducted. These 10 HLA-homozygous iPSC lines match 41.07% of the Korean population. Comparative analysis of HLA population data shows that they are also of use in other Asian populations, such as Japan, with some limited utility in ethnically diverse populations, such as the UK. Taken together, the generation of the 10 most frequent Korean HLA-homozygous iPSC lines serves as a useful pointer for the development of optimal methods for iPSC generation and quality control and indicates the benefits and limitations of collaborative HLA driven selection of donors for future stocking of worldwide iPSC haplobanks. Stem Cells 2018;36:1552-1566.

HLA‐A, ‐B, ‐C, ‐DRB1, and ‐DQB1 allele and haplotype frequencies: An analysis of umbilical cord blood units at the Barcelona Cord Blood Bank

“…24,25,41 Several studies have analyzed the optimal number of homozygous CB units needed to cover a large part of the population. 22,[42][43][44][45] In our study, 229 three-locus haplotypes and 319 five-locus haplotypes matched 100% of the population. In other words, a corresponding number of homozygous CB units would be needed to provide coverage to a cohort of patients living in our region with the haplotype frequencies described in this study.…”

“…Finally, considering that CB is a source of iPS in regenerative medicine, the recruitment of HLA‐homozygous units should facilitate the creation of allogeneic iPS banks . Several studies have analyzed the optimal number of homozygous CB units needed to cover a large part of the population . In our study, 229 three‐locus haplotypes and 319 five‐locus haplotypes matched 100% of the population.…”

Impact of Homozygous Conserved Extended HLA Haplotype on Single Cord Blood Transplantation: Lessons for Induced Pluripotent Stem Cell Banking and Transplantation in Allogeneic Settings

“…Induced pluripotent stem cells (iPSCs) [1] have been applied to clinical regenerative cell therapies such as the macular degeneration of the retina [2], spinal cord injury [3], and heart failure [4]. Because the use in autologous settings is hampered by the excessive time and cost requirements of the individual production of iPSCs, an iPSC banking system that collects HLA typed cells from cord blood banks, marrow donor registries, and HLA matched platelet donor registries has been proposed [5][6][7][8], and tissue transplantation generated from iPSCs through banking in allogeneic settings has recently been performed [9]. iPSC banks collect cord blood cells or peripheral blood cells with homozygous HLA (HLA-homo) haplotype (HP), because HLA-homo iPSCs might not be rejected in transplantation with 1 HLA HP-matched in the host-versus-graft (HVG) direction.…”

Development of genetic quality tests for good manufacturing practice-compliant induced pluripotent stem cells and their derivatives

“…Once product safety and functional issues have been adequately addressed, an additional factor that should be considered is the human leucocyte antigen (HLA) type of the product cells to be used for allogenic transplantation. Thus, HLA-matched hiPSC lines, which could present broad applications in global and regional populations, have been suggested for use in allogenic transplantation 12,13 . Accordingly, a haplobank could provide high-quality homozygous HLA-matched hiPSC lines, thereby saving time and reducing costs while maximizing coverage 14 .…”