Hematology, Immunology and Infectious Disease

Neonatology Questions and Controversies

Robin K Ohls, Akhil Maheshwari

• Publisher: Elsevier
• Year: 2018
• ISBN:
  9780323568470
• Edition: 3
• Topic: Medizin
• Subtopic: Perinatologie & Neonatologie

Dr. Richard Polin's Neonatology Questions and Controversies series highlights the most challenging aspects of neonatal care, offering trustworthy guidance on up-to-date diagnostic and treatment options in the field. In each volume, renowned experts address the clinical problems of greatest concern to today's practitioners, helping you handle difficult practice issues and provide optimal, evidence-based care to every patient.

Chapter 1

Stem Cell Therapy in Neonates—the Time Has (Almost) Come

Lars Mense, MD, and Bernard Thébaud, MD

• The introduction of different types of stem cells (mesenchymal stromal cells, endothelial colony-forming cells, human amnion epithelial cells) in animal models of neonatal diseases such as bronchopulmonary dysplasia, intraventricular hemorrhage, neonatal stroke, and hypoxic-ischemic encephalopathy reveal promising improvements.

• The most important mechanism of stem cell action includes paracrine, immunomodulatory effects. Cell engraftment is generally low.

• A first phase I study with mesenchymal stromal cells for bronchopulmonary dysplasia has demonstrated feasibility and short-term safety.

• Cell-free treatments with conditioned media or exosomes might offer further options in the future.

• The time has come for a careful translation of stem cell research into the clinic. Rigorous study designs and long-term follow-up are essential.

• Further knowledge about stem cell biology and the mechanism of action of therapeutic cell products is required to realize the potential of regenerative medicine in neonatology.

Premature birth complications have become the leading cause of death in children younger than 5 years.¹ Bronchopulmonary dysplasia (BPD) and intraventricular hemorrhage (IVH) remain the most frequent complications and contribute significantly to mortality and morbidity of the extremely premature neonate. Hypoxic-ischemic encephalopathy and neonatal stroke are leading causes of mortality and morbidity in term neonates. Congenital defects of the cardiovascular or respiratory system represent a third group of neonatal diseases with a high medical and economic burden.

Cell-based therapies offer a new field of therapeutic interventions and may represent a paradigm shift in perinatal medicine. Significant therapeutic benefits have been demonstrated in animal studies, and cell-based therapies are on the verge of clinical translation. Caution is warranted, however, because (1) cell-based therapy for regenerative purposes represents a disruptive innovation, (2) mechanisms of action are still not completely understood, and (3) the translation from mouse to human is not without risks.

This chapter briefly introduces the different types of stem cells considered thus far, summarizes experimental data on stem cell treatment in animal models, reviews the first human trials, and discusses open questions and considerations for future research.

Stem cells: important in development and disease

Stem cells are a crucial part of the embryonic and fetal development in humans but also participate in disease processes (Fig. 1.1). They are defined by two characteristics²:

• 1. Potency, describing the ability to form cells of a single cell line (unipotent) up to all cell lines of an organism (pluripotent).
• 2. Self-renewal potential, describing the ability to preserve a stem cell pool by asymmetric or symmetric cell division.

Stem cell division can produce one daughter stem cell and one differentiated somatic cell (asymmetric cell division) or can lead to two daughter stem cells or two differentiated cells (symmetric cell division).³ Although symmetric cell division facilitates rapid production of differentiated cells, the stem cell pool might become exhausted and impair repair capacity. This underlines the fundamental idea of stem cell therapy. After more than 50 years of experience with hematopoietic stem cells for leukemia and severe combined immunodeficiency, their niche cells—mesenchymal stromal cells (MSCs)—have moved into the focus of regenerative medicine for nonhematologic diseases.

Mesenchymal stromal cells: orchestrator of immune response and healing processes

In 1970, Friedenstein et al.⁴ first described MSCs as fibroblastoid cells from bone marrow (BM). MSCs are a heterogeneous population of plastic-adherent cells demonstrating self-renewal and potency to differentiate into the three typical mesenchymal tissues, of bone, cartilage, and fat.⁵ Over the years, MSCs were discovered in several other organs, including the placenta,⁶ Wharton’s jelly of the human umbilical cord (hUC),⁷ blood,⁸ and the lung.⁹ In 2006 a consensus conference established minimal criteria to define MSCs, as follows¹⁰:

• 1. Adherence to plastic
• 2. Positivity for the cell surface markers CD73, CD105, and CD90
• 3. Absence of CD45, CD34, CD14/CD11b, CD79a/CD19, and HLA-DR
• 4. In vitro differentiation into chondroblasts, osteoblasts, and adipocytes

MSCs interact with the immune system in many ways and can boost or suppress an immune response. Their effect depends on the balance of proinflammatory and anti-inflammatory markers. However, MSCs may also contribute to healing processes by modulating scar formation, cell survival, angiogenesis, and release of growth factors.¹¹

Endothelial colony-forming cells: when angiogenesis counts

Impaired angiogenesis is a cornerstone of several neonatal diseases, including BPD and congenital diaphragmatic hernia, which are often complicated by pulmonary hypertension.¹² Endothelial progenitor cells (EPCs) were isolated from peripheral blood first and showed differentiation potential into endothelial cells and homing to areas of angiogenesis.¹³ This group of EPCs was later refined as early-outgrowth EPCs and late-outgrowth endothelial colony-forming cells (ECFCs). ECFCs are clonogenic, display self-renewal, and can form de-novo blood vessels.¹⁴

ECFCs can be isolated from human and rodent lung tissue and show functional deterioration in experimental BPD.^15,16 They are increased in preterm umbilical cord blood (UCB), proliferate faster, but are also more sensitive to hyperoxia than ECFCs from term UCB.¹⁷ They seem to be involved in the pathogenesis of BPD; preterm newborns who develop moderate or severe BPD have a lower number of ECFCs in their UCB.¹⁸

UCB-ECFC function is disturbed in newborns with congenital diaphragmatic hernia: Their ECFCs show less self-renewal, less in vivo vasculogenesis, slower growth, and an impaired response to vascular endothelial growth factor (VEGF).¹⁹ Data on the number of circulating ECFCs in cord blood are conflicting.^19-21

The therapeutic potential of ECFCs could be limited by their immunogenicity,²² although this theory was recently questioned.²³ Further assessment of allogeneic injections of ECFCs is needed before a clinical translation seems justified. ECFC-derived exosomes (nano-sized extracellular vesicles) might offer an alternative, but their immunogenicity requires further studies as well.²⁴

Fig. 1.1 Sources of stem cells and their targeted organs.Stem cells were isolated from organs depicted in light color but not used in regenerative medicine. ECFC, Endothelial colony-forming cells; hAEC, human amnion epithelial cells, MSC, mesenchymal stromal cells.

Amnion epithelial cells—don’t discount the placenta

The amniotic membrane, the innermost layer of the placenta, is a very rich source of amnion epithelial cells. AECs express stem cell markers and are able to differentiate into the three germ layers without developing teratomas.²⁵ Amniotic membranes already are used for burns and ocular surgery in humans, providing some safety data.²⁶ Human AECs (hAECs) have anti-inflammatory effects²⁶ and can be incubated with exogenous surfactant ex vivo without triggering cell differentiation, which might allow a co-administration of AEC and surfactant in extreme preterms.²⁷ Functional differences seem to exist between term and preterm hAECs.²⁸ Their immunogenic potential is low, and allogeneic transplantation seems possible.²⁶

Bronchopulmonary dysplasia and stem cell therapy

The histologic picture of BPD is characterized by alveolar simplification and decreased pulmonary vascularization and is asso...