The field of regenerative medicine is dedicated to the study of repairing, replacing or regenerating damaged human cells, tissues or organs to restore or establish normal function [1]. The ultimate goal, of course, is to develop methods to treat previously untreatable conditions and improve outcomes of injuries and diseases for which traditional therapies are inadequate. Regenerative approaches including novel medical devices, tissue engineering and generation of artificial organs, and cellular therapies are all currently in development and/or under investigation across a wide range of disciplines.

Investigations in cellular therapy – utilizing cells therapeutically to not just replace lost or damaged cells, but to affect/change existing cells and ongoing disease processes – have increased rapidly and have numerous potential applications. Sources of cells for such purposes vary extensively, each with their own associated potential risks and benefits. This article will focus on the use of umbilical cord blood (CB) as a source of cells for emerging cellular therapies, summarize the scope of ongoing clinical trials, and highlight their potential applications in neurologic conditions.

Umbilical cord blood as a source of cells for regenerative therapies

As a source of cells for developing therapeutic cell products, CB has several unique qualities. CB is an abundantly available source of cells that can be harvested at no risk to the mother or infant donor. It is routinely collected, cryopreserved and banked, making it readily available and accessible on demand. Many infectious agents are much less common in newborns and donating mothers undergo extensive donor screening, making CB a relatively safe source of cells with a low risk of transmitting infections. Importantly, CB is also a non-controversial source of cells as it has historically been discarded as medical waste after birth along with the placenta.

Umbilical CB is a well-established source of cells for hematopoietic stem cell transplantation (HSCT), in which donor CB cells are used to replace the recipient’s hematopoietic and immune systems. Compared to bone marrow, CB is more readily available, requires less stringent HLA-matching, has a lower incidence of graft-versus-host disease, and is less likely to transmit infections via latent viruses. As such, CB has made HSCT available for many patients lacking a suitable bone marrow donor and has become the preferred donor source in certain clinical scenarios. In over 30 years of use in allogeneic, unrelated HSCT, CB has not been shown to cause any teratomas or solid tumors [2].

After HSCT, donor CB cells engraft in the bone marrow and distribute throughout the body. In fact, CB donor-derived tissue-specific cells have been identified in multiple organs in both animals and humans after HSCT, including the liver [3], lung, pancreas [3,4], skeletal muscle [5] and brain [6], indicating that transplanted CB cells are capable of repopulating more than just the hematopoietic system [7,8]. This may be due to the presence of a true embryonic-like stem cell in CB or small numbers of committed but tissue-specific, non-hematopoietic progenitors. Nonetheless, while CB cells have the ability to differentiate into tissue-specific cells and integrate into host organs, there is growing evidence that their therapeutic effects in settings other than traditional HSCT, may result more from their ability to initiate tissue repair by activating host cells via paracrine effects.

Scope of ongoing studies

The relative ease of collection, processing, testing and storage of CB along with its potential therapeutic properties, make it an attractive source of cells for regenerative medicine applications across many disciplines. In fact, a recent systematic review identified 57 published clinical studies involving a total of 814 patients that utilized CB as cell therapy for novel indications in regenerative therapy and immune modulation [9], and more are ongoing. Table 1 summarizes currently available clinical trials registered with clinicaltrials.gov that are investigating CB and CB-derived products for regenerative purposes. Most are studying the use of donor, allogeneic CB administered as unmanipulated whole CB (total nucleated cells or TNC), mononuclear cells (MNC) or CB-derived mesenchymal stromal cells (MSC). The most common method of delivery is intravenous infusion, presumably based on both ease of administration and the assumption that the CB cells distribute throughout the body via the blood and affect the intended disease process through the release of chemical signals.

Clinical trials of CB as regenerative therapies are being conducted throughout the world but are concentrated heavily in Asia and the USA (Figure 1Map of geographic regions where cell therapy studies utilizing umbilical cord blood are being conducted. The majority of clinical trials are performed in Asia and the USA.). Most lines of investigation are still in the early stages as evidenced by the fact that the majority of clinical studies are Phase 1 or combined Phase 1/2 trials (n = 34). Studies range in clinical indication from pulmonary diseases to infertility to orthopedic conditions, but the most common area of investigation is neurologic conditions including stroke, cerebral palsy and hypoxic ischemic encephalopathy.

Potential neurologic mechanisms & applications of umbilical cord blood

Many neurologic diseases and injuries have long been considered irreversible and untreatable, with therapies focused on alleviating symptoms as opposed to treating the underlying cause. Traditionally, the brain was thought of as a static organ with an extremely limited ability to regenerate, repair or adapt to injury. Advances in neuroscience have challenged the conventional wisdom, however, discovering that the brain does indeed possess a limited capacity for self-renewal. This fundamental conceptual change has launched a new wave of research to determine how to harness and manipulate that ability to address previously untreatable neurologic conditions. Given the complex, intricate circuitry and microenvironments of the nervous system, biologic cell-based therapies have garnered substantial attention as potential treatments to repair damage, regain function and improve quality of life in patients with neurological disorders.

There are multiple mechanisms by which CB cells may affect cell and tissue repair in neurologic conditions, and different ones may be operative in different conditions or at different times during the course of injury and repair. Acutely, CB cells may deliver trophic factors that provide anti-inflammatory and neuroprotective effects thereby enhancing the survival of host cells [10-13]. They may also increase the plasticity of the injured and recovering brain by enhancing synaptogenesis, angiogenesis and endogenous repair mechanisms and/or by inducing migration and proliferation of existing neural stem cells [6,14,15]. To a lesser degree, CB cells may also migrate, integrate, proliferate, and differentiate into ‘replacement’ neuronal and glial cells and play a role in remyelination [16]. Finally, CB-derived cells could also potentially serve as a vehicle to deliver neuroprotective and restorative factors or signal endogenous cells to act in a targeted way toward damaged brain tissue. These mechanisms have been observed in numerous preclinical models of ischemic, genetic and neurodegenerative conditions of the central nervous system.

Currently, clinical trials of CB therapies are being conducted in patients with acquired brain injuries such as stroke (n = 3), cerebral palsy (n = 6), hypoxic ischemic encephalopathy (n = 4) and intraventricular hemorrhage (n = 1), genetic diseases that affect the brain (n = 1), neurodegenerative conditions (n = 1), and autism spectrum disorder (n = 1). The most common route of administration is intravenous, though intrathecal and direct injections are also practiced. Many published reports have suggested potential benefits [9], though few prospective, controlled studies have been completed.

The indication for which the most prospective data of CB therapy is available is cerebral palsy. In a randomized, double-blind, placebo-controlled trial of 63 children aged 1–6 years old with cerebral palsy conducted by our group at Duke University, there was no difference in motor improvement between the study groups as a whole. However, patients receiving a precryopreservation total nucleated cell dose of ≥2.5 x 10⁷ cells/kg demonstrated greater improvement of motor function and normalized whole brain connectivity than subjects receiving smaller cell doses. This finding is consistent with two other randomized trials of CB therapy in children with CP, both conducted in Korea using allogeneic CB [17,18]. One of those studies demonstrated greater improvement on motor and cognitive scales in patients who received a precryopreservation cell dose of ≥3 x 10⁷/kg + erythropoietin versus those who received erythropoietin alone or placebo. They also noted a dose correlation, with higher doses associated with greater improvement [17]. The second study showed similar results in 36 children randomized to treatment with CB or placebo [18]. Additional studies of CB for the treatment of cerebral palsy are being conducted in Australia, China, Korea and the USA.

Autologous CB infusions are being studied in newborn babies with hypoxic ischemic encephalopathy at birth. In a Phase 1 trial conducted at Duke, fresh, non-cryopreserved autologous CB infused in 1, 2 or 4 doses of 1-5 x 10⁷ nucleated cells/kg within the first 72 hours of life in babies with moderate-to-severe encephalopathy qualifying for systemic hypothermia [19]. These babies were compared to a concomitant group of babies treated at Duke who were cooled but did not receive CB cells. Infusions were found to be safe in these critically ill babies, and babies receiving cells had increased survival rates to discharge (100 vs 85%; p = 0.20) and improved function at one year of age (74 vs 41% with development in the normal range; p = 0.05). A Phase 2 multicenter, randomized controlled trial is currently underway in the USA, and additional studies of CB infusion in babies with hypoxic ischemic encephalopathy are ongoing in China and Japan.

Other prospective randomized studies of CB infusion are being performed for adults with acute ischemic stroke and children with autism spectrum disorder. Infusion in these populations was shown to be safe in early reports [20,21], and the current investigations will shed light on the potential for therapeutic benefit.

Translational insight

Regenerative medicine represents a new frontier with the potential to transform the way diseases are understood, inspire innumerable lines of scientific investigation, and revolutionize the treatment of a variety of conditions for which current options are limited, inadequate or non-existent. CB is an attractive source of cells for such therapies due to its ease of collection, ability to be cryopreserved indefinitely, safe track record of use in the clinic and noncontroversial nature. In order to capitalize on these features and to make regenerative therapies available to the population at large, the development of allogeneic, off-the-shelf products that can be reliably manufactured, accessible and easily administered without the need for significant immunosuppression will be essential. Expanded indications for CB use in this manner would likely also necessitate changes in the current structure of public and private CB banking. However, data from additional human studies is needed to fully define the safety and efficacy of regenerative CB therapies and to determine the clinical applications in which its use is justified.

Financial & competing interests disclosure

The author has no relevant financial involvement with an organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock options or ownership, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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Affiliations

Jessica M Sun
Robertson Clinical and Translational Cell Therapy Program, Duke University Medical Center, NC, USA.

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