Paradigms of adult stem cell therapy for type 1 diabetes in mice.

Abstract

Hardly a day passes without news of stem cells. Stem cell therapy implies the replacement of diseased or lost cells from the progeny of stem cells that differentiate into the required phenotypes. Stem cells have the capacity to divide asymmetrically, that is, yielding one identical ‘daughter’ stem cell and a second daughter cell that proceeds towards terminal differentiation. Thus, stem cells are theroretically endlessly self-renewing and from thence derives their hoped-for uses. There are two large groups of stem cells: embryonic stem cells (stem cells derived from early embryonic stages) and adult stem cells (stem cells found in the postnatal organism). Reconstitution of bone marrow by hematopoietic stem cell infusion is an established practice in the treatment of certain cancers and of certain disorders of hematopoiesis. Recently, bone marrow and other hematopoietic organs (liver and spleen) have been shown to harbor cells that possess the capacity to enter extramedullary tissues and to differentiate into functional parenchymal cells of the respective tissue, such as the liver, intestinal, skin and bronchial epithelia (1, 2), skeletal (3, 4), heart (5, 6) muscle and cells of the central nervous system (7, 8). These observations are not limited to experimental rodent models but are also made in biopsy material of human recipients of bone marrow transplantation (9, 10). Several recent reports have uncovered the possibility of using adult stem cells from hematopoietic organs for the replacement of pancreatic endocrine cells and the treatment of type 1 diabetes mellitus (11 –15). We summarize these findings as they represent different, albeit similar, paradigms of cellular regeneration in adult diabetic organisms. In a first report, Ianus et al. (11) demonstrated that in mice, cells from transplanted bone marrow engraft into the pancreatic islets. A genetic mouse model allowed identification of transplanted bone marrowderived cells by virtue of a fluorescent protein that is expected to be expressed in cells if they transcribe insulin. Fluorescent cells were found in pancreatic islets of recipient mice approximately 1 –2 months after bone marrow transplantation. Importantly, fluorescent cells were also positive for the Y chromosome that came from the male donor in the female bone marrow recipient (Fig. 1A). These donor-derived engrafted cells express insulin and other genetic markers typical of pancreatic beta cells. When tested in isolated culture conditions, the bone marrow-derived cells secrete insulin in response to a physiological glucose stimulus, and show intracellular calcium fluctuations reminiscent of pancreatic beta cells. However, 1–2 months after bone marrow transplantation, only about 1–3% of the islet cells originate from the transplanted bone marrow. This rate of engraftment does not account for the normal estimated turnover of 30 days of the endocrine cells in an islet (16). Additional studies demonstrated that cell fusion is not a likely explanation for the observed phenomenon of differentiation of bone marrow-derived cells into pancreatic endocrine cells. In a second report by Hess et al. (12), streptozotocindiabetic mice were lethally irradiated and transplanted with bone marrow from donors that ubiquitously express green fluorescent protein (GFP). Whereas control mice remained hyperglycemic and showed increased mortality, bone marrow-transplanted mice were normoglycemic, had normal insulin production after 17 days and had an increased survival rate at day 42 (75 – 85% vs 0–50%). Increases in serum insulin correlated with reduction in blood glucose. Furthermore, the investigators showed that bone marrow cells that express c-kit – one of the ‘stem cell markers’ – as a surface marker could, when transplanted, lead to reduction in glycemia, whereas c-kit-negative cells had no effect. Comparison of engraftment into liver and pancreas revealed that bone marrow-derived cells engrafted preferentially into the streptozotocin-damaged pancreas. In the pancreas, bone marrow-derived cells were found in two regions: the ducts and the islets. In the islets, most bone marrow-derived cells did not contain insulin, although a small number of bone marrowderived cells also contained insulin protein. These insulin-positive cells were found only in streptozotocin-diabetic bone marrow recipients. However, the insulin-positive cells did not coexpress the beta-cellspecific transcription factor PDX-1. The authors speculate that the insulin-positive cells may have been incorporating insulin from their surrounding environment rather than producing insulin themselves. Because of the small number of donor-derived, insulin-positive cells in the face of normoglycemia in bone H IG H L IG H T European Journal of Endocrinology (2004) 150 415–419 ISSN 0804-4643