Cell transplantation for gastroparesis

Introduction

Normal gastric motor function requires coordinated interaction between the central nervous system (CNS), the enteric nervous system (ENS), interstitial cells of Cajal (ICC), and smooth muscle cells (SMCs). Gastroparesis is a multifactorial neuromuscular disorder involving dysfunction at various levels of this network. For example, vagal dysfunction, disruption of the ENS (particularly loss of nitrergic neurons), smooth muscle abnormalities, and deficits in ICC networks have all been implicated in the pathogenesis of diabetic gastroparesis . Given this complexity, it is not surprising that our current therapies, whether pharmacologic, device-based (electrical stimulation), or surgical (gastrectomy or pyloromyotomy) fail to repair this functional interaction. An ideal approach would be to replace or replenish permanently impaired cells while maintaining the spatial and temporal function of the neuromuscular network. Given recent advances in stem cell biology, cell-based therapies offer promise.

In this chapter, we will discuss the progress that has been made in the discovery of stem cell populations that may be suitable for cell-based therapies for gastroparesis, and highlight challenges that remain to bring such therapies to patients. We will focus on CNS-derived neural stem cells (CNS-NSCs), enteric neural stem cells (ENSCs) derived from the gut, mesenchymal stem cells (MSCs) and progenitors of ICCs, and pluripotent stem cells ( Fig. 39.1 ). We will also discuss technical considerations to enhance stem cell engraftment.

Central nervous system-derived neural stem cells

Isolated from distinct regions of the brain, namely the hippocampus and subventricular zone , CNS-NSCs are multipotent “adult” stem cells that have remarkable plasticity when transplanted to other tissues—including the gut. They are capable of differentiating into nNOS-expressing neurons, a key neuronal subtype in the ENS, both in vitro and in vivo after injection into rodent stomachs . CNS-NSCs can be induced towards an enteric phenotype by co-culturing with dissected longitudinal muscle and myenteric plexus gut tissue . Upon differentiation, these neurons exhibited a negative resting membrane potential, the presence of voltage-gated sodium channels, and after-hyperpolarization current characteristic of enteric intrinsic primary afferent neurons (IPANs) . CNS-NSCs appear capable of homing to sites of injury in the gut. For instance, when injected intravenously into mice following intestinal surgery, they migrated to and differentiated into neurons at the surgical anastomosis . Importantly, in an animal model of gastroparesis (nNOS ^−/− mice) , CNS-NSCs transplanted into the stomach partially restored gastric function after 1 week . However, for unclear reasons, there was not sustained engraftment, with significant cell loss 2–4 weeks after transplantation. Unfortunately, the lack of a readily accessible source for CNS-NSCs, particularly given the limited potential of adult stem cells to be propagated in vitro , provides a significant challenge for their use in cell-based therapies.