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Cleveland, OH, United States

Ratajczak M.Z.,University of Louisville | Suszynska M.,Pomeranian Medical University | Pedziwiatr D.,Pomeranian Medical University | Mierzejewska K.,Pomeranian Medical University | Greco N.J.,Cleveland Cord Blood Center
Pediatric Endocrinology Reviews | Year: 2012

Umbilical cord blood-derived very smalt embryonic-like stem cells (UCB-VSELs) are the most primitive stem cells circulating in fetal peripheral blood. These very rare cells slightly smaller than red blood cells i) become mobilized during delivery, ii) are enriched in fraction of CD133+ Lin-CD45- cells iii) express markers of pluripotent stem cells (e.g., Oct4, Nanog, and SSEA-4) and iv) display a distinct morphology characterized by a high nuclear/cytoplasmic ratio and undifferentiated chromatin. We envision that VSELs are released into neonatal peripheral blood as a migrating population of stem cells involved in regeneration of tissues that become damaged in the process of delivery. They may also be responsible for the occurrence of fetal-maternal chimerism. Our most recent data suggest that UCB-VSELs exhibit some characteristics of long-term repopulating hematopoietic stem cells (LT-HSCs). We propose that UCB-VSELs may eventually be employed as a source of pluripotent stem cells in regenerative medicine.

Ballen K.K.,MA General Hospital | Logan B.R.,Medical College of Wisconsin | Laughlin M.J.,Cleveland Cord Blood Center | He W.,Medical College of Wisconsin | And 26 more authors.
Biology of Blood and Marrow Transplantation | Year: 2015

Variations in cord blood manufacturing and administration are common, and the optimal practice is not known. We compared processing and banking practices at 16 public cord blood banks (CBB) in the United States and assessed transplantation outcomes on 530 single umbilical cord blood (UCB) myeloablative transplantations for hematologic malignancies facilitated by these banks. UCB banking practices were separated into 3 mutually exclusive groups based on whether processing was automated or manual, units were plasma and red blood cell reduced, or buffy coat production method or plasma reduced. Compared with the automated processing system for units, the day 28 neutrophil recovery was significantly lower after transplantation of units that were manually processed and plasma reduced (red cell replete) (odds ratio, .19; P=001) or plasma and red cell reduced (odds ratio, .54; P=05). Day 100 survival did not differ by CBB. However, day 100 survival was better with units that were thawed with the dextran-albumin wash method compared with the "no wash" or "dilution only" techniques (odds ratio, 1.82; P=04). In conclusion, CBB processing has no significant effect on early (day 100) survival despite differences in kinetics of neutrophil recovery. © 2015 American Society for Blood and Marrow Transplantation.

Brunstein C.G.,University of Minnesota | McKenna D.H.,University of Minnesota | DeFor T.E.,University of Minnesota | Sumstad D.,Molecular and Cellular Therapy Center | And 6 more authors.
Biology of Blood and Marrow Transplantation | Year: 2013

Preclinical data showed that priming CD34+ hematopoietic progenitor cells with complement fragment 3a (C3a) improved homing and engraftment. Thus, we hypothesized that priming of umbilical cord blood (UCB) hematopoietic progenitors with C3a would facilitate homing and could potentially be used to address the need for improved engraftment after UCB transplantation. We primed 1 of 2 UCB units for double UCB transplantation after nonmyeloablative conditioning. This design provided adequate safety and the potential to observe skewed long-term chimerism in favor of the C3a-primed unit as a surrogate measure of efficacy. C3a priming of 1 UCB unit did not result in infusional toxicity. Increased grades 1 to 3 hypertension were the only infusional adverse events observed in 9 (30%) patients. We observed no activation of inflammatory or coagulation pathways downstream of C3a. As tested, C3a priming did not impair engraftment, but did not skew chimerism toward the treated unit. As compared with historical controls, mortality and survival were not adversely affected. Thus, before any additional clinical studies, C3a priming to promote engraftment will require further preclinical optimization. © 2013 American Society for Blood and Marrow Transplantation.

Ratajczak M.Z.,University of Louisville | Kucia M.,University of Louisville | Jadczyk T.,Medical University of Silesia, Katowice | Greco N.J.,Cleveland Cord Blood Center | And 3 more authors.
Leukemia | Year: 2012

Although regenerative medicine is searching for pluripotent stem cells that could be employed for therapy, various types of more differentiated adult stem and progenitor cells are in meantime being employed in clinical trials to regenerate damaged organs (for example, heart, kidney or neural tissues). It is striking that, for a variety of these cells, the currently observed final outcomes of cellular therapies are often similar. This fact and the lack of convincing documentation for donor-recipient chimerism in treated tissues in most of the studies indicates that a mechanism other than transdifferentiation of cells infused systemically into peripheral blood or injected directly into damaged organs may have an important role. In this review, we will discuss the role of (i) growth factors, cytokines, chemokines and bioactive lipids and (ii) microvesicles (MVs) released from cells employed as cellular therapeutics in regenerative medicine. In particular, stem cells are a rich source of these soluble factors and MVs released from their surface may deliver RNA and microRNA into damaged organs. Based on these phenomena, we suggest that paracrine effects make major contributions in most of the currently reported positive results in clinical trials employing adult stem cells. We will also present possibilities for how these paracrine mechanisms could be exploited in regenerative medicine to achieve better therapeutic outcomes. This approach may yield critical improvements in current cell therapies before true pluripotent stem cells isolated in sufficient quantities from adult tissues and successfully expanded ex vivo will be employed in the clinic. © 2012 Macmillan Publishers Limited.

Ratajczak J.,University of Louisville | Ratajczak J.,Pomeranian Medical University | Zuba-Surma E.,University of Louisville | Klich I.,University of Louisville | And 7 more authors.
Leukemia | Year: 2011

A population of CD133+ Lin- CD45- very small embryonic/epiblast-like stem cells (VSELs) has been purified by multiparameter sorting from umbilical cord blood (UCB). To speed up isolation of these cells, we employed anti-CD133+-conjugated paramagnetic beads followed by staining with Aldefluor to detect aldehyde dehydrogenase (ALDH) activity; we subsequently sorted CD45-/GlyA-/CD133 +/ALDHhigh and CD45-/GlyA-/ CD133+/ALDHlow cells, which are enriched for VSELs, and CD45- /GlyA- /CD133+/ALDHhigh and CD45-/GlyA- /CD133+ /ALDHlow cells, which are enriched for hematopoietic stem/progenitor cells (HSPCs). Although freshly isolated CD45- VSELs did not grow hematopoietic colonies, the same cells, when activated/expanded over OP9 stromal support, acquired hematopoietic potential and grew colonies composed of CD45- hematopoietic cells in methylcellulose cultures. We also observed that CD45 -/GlyA-/CD133+/ALDHhigh VSELs grew colonies earlier than CD45-/GlyA-/CD133+ /ALDHlow VSELs, which suggests that the latter cells need more time to acquire hematopoietic commitment. In support of this possibility, real-time polymerase chain reaction analysis confirmed that, whereas freshly isolated CD45- /GlyA-/CD133+/ALDHhigh VSELs express more hematopoietic transcripts (for example, c-myb), CD45 -/GlyA-/CD133+ /ALDHlow VSELs exhibit higher levels of pluripotent stem cell markers (for example, Oct-4). More importantly, hematopoietic cells derived from VSELs that were co-cultured over OP9 support were able to establish human lympho-hematopoietic chimerism in lethally irradiated non-obese diabetic/severe combined immunodeficiency mice 4-6 weeks after transplantation. Overall, our data suggest that UCB-VSELs correspond to the most primitive population of HSPCs in UCB. © 2011 Macmillan Publishers Limited. All rights reserved.

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