Background aims. Human dermal ABCB5-expressing mesenchymal stromal cells (ABCB5 + MSCs) represent a promising candidate for stem cell based therapy of various currently uncurable diseases in several fields of regenerative medicine. We have developed and validated a method to isolate, from human skin samples, and expand ABCB5 + MSCs that meet the guideline criteria of the International Society for Cellular Therapy. We are able to process these cells into a Good Manufacturing Practice conforming, MSC-based advanced-therapy medicinal product. Methods. To support the development of ABCB5 + MSCs for potential therapeutic topical, intramuscular and intravenous administration, we have tested our product in a series of Good Laboratory Practice compliant nonclinical in-vivo studies addressing all relevant aspects of biosafety, including potential long-term persistence and proliferation, distribution to nontarget tissues, differentiation into undesired cell types, ectopic tissue formation, tumor formation and local tissue reaction. Results. (i) Subcutaneous application of 1 × 10 7 ABCB5 + MSCs/animal and intravenous application of 2 × 10 6 ABCB5 + MSCs/animal, respectively, to immunocompromised mice did not result in safety-relevant biodistribution, persistence or proliferation of the cells; (ii) three monthly subcutaneous injections of ABCB5 + MSCs at doses ranging from 1 × 10 5 to 1 × 10 7 cells/animal and three biweekly intravenous injections of 2 × 10 6 ABCB5 + MSCs/animal, respectively, to immunocompromised mice were nontoxic and revealed no tumorigenic potential; and (iii) intramuscular injection of 5 × 10 6 ABCB5 + MSCs/animal to immunocompromised mice was locally well tolerated. Discussion. The present preclinical in vivo data demonstrate the local and systemic safety and tolerability of a novel advanced-therapy medicinal product based on human skin-derived ABCB5 + MSCs.

Background aim: Mesenchymal stromal cells (MSCs) hold promise for the treatment of tissue damage and injury. However, MSCs comprise multiple subpopulations with diverse properties, which could explain inconsistent therapeutic outcomes seen among therapeutic attempts. Recently, the adenosine triphosphate-binding cassette transporter ABCB5 has been shown to identify a novel dermal immunomodulatory MSC subpopulation. Methods: The authors have established a validated Good Manufacturing Practice (GMP)-compliant expansion and manufacturing process by which ABCB5 + MSCs can be isolated from skin tissue and processed to generate a highly functional homogeneous cell population manufactured as an advanced therapy medicinal product (ATMP). This product has been approved by the German competent regulatory authority to be tested in a clinical trial to treat therapy-resistant chronic venous ulcers. Results: As of now, 12 wounds in nine patients have been treated with 5 £ 10 5 autologous ABCB5 + MSCs per cm 2 wound area, eliciting a median wound size reduction of 63% (range, 32À100%) at 12 weeks and early relief of pain. Conclusions: The authors describe here their GMP-and European Pharmacopoeia-compliant production and quality control process, report on a pre-clinical dose selection study and present the first in-human results. Together, these data substantiate the idea that ABCB5 + MSCs manufactured as ATMPs could deliver a clinically relevant wound closure strategy for patients with chronic therapy-resistant wounds.

Although the molecular machinery and mechanism of cell secretion in acinar cells of the exocrine pancreas is well documented and clear, only recently has the pharmacophysiology of pancreatic exocrine secretion come to light. Therefore, we focus in this article on the current understanding of the pharmacophysiology of pancreatic exocrine secretion. The pancreatic secretory response to ingestion of a meal is mediated via a complex interplay of neural, humoral and paracrine mediators. A major role in the control of the intestinal phase of pancreatic secretion is attributed to vago-vagal enteropancreatic reflexes. In the scheme of this control mechanism, afferents originating in the duodenal mucosa, and efferents mediating central input on the pancreatic ganglia, activate intrapancreatic postganglionic neurons. Experiments utilizing specific receptor antagonists demonstrate the involvement of both muscarinic M1 and M3 receptors expressed in pancreatic acinar cells. Cholecystokinin (CCK), originally implicated in the humoral secretion of pancreatic enzymes, through a direct action on acinar CCK receptors, is also essential to the enteropancreatic reflex mechanism. CCK stimulation of the exocrine pancreatic secretion through excitation of sensory afferents of the enteropancreatic reflexes, is a paracrine mode of CCK action, and is probably the only one in humans and the predominant one in rats. In dogs, however, CCK acts on the pancreas via both the humoral and a paracrine route. More recent experiments suggest further possible sites of CCK action. Additionally, at the brain stem, vago-vagal enteropancreatic reflexes may be modulated by input from higher brain centres, particularly the hypothalamic-cholinergic system in the tonic stimulation of preganglionic neurons of the dorsal motor nucleus of the vagus projecting into the pancreas.