Combinatorial Human Progenitor Cell Transplantation Optimizes Islet Regeneration Through Secretion of Paracrine Factors

Abstract

Transplanted human bone marrow (BM) and umbilical cord blood (UCB) progenitor cells activate islet-regenerative or revascularization programs depending on the progenitor subtypes administered. Using purification of multiple progenitor subtypes based on a conserved stem cell function, high aldehyde dehydrogenase (ALDH) activity (ALDH(hi)), we have recently shown that transplantation of BM-derived ALDH(hi) progenitors improved systemic hyperglycemia and augmented insulin secretion by increasing islet-associated proliferation and vascularization, without increasing islet number. Conversely, transplantation of culture-expanded multipotent-stromal cells (MSCs) derived from BM ALDH(hi) cells augmented total beta cell mass via formation of beta cell clusters associated with the ductal epithelium, without sustained islet vascularization. To identify paracrine effectors produced by islet-regenerative MSCs, culture-expanded BM ALDH(hi) MSCs were transplanted into streptozotocin-treated nonobese diabetic/severe combine immune deficient (SCID) mice and segregated into islet-regenerative versus nonregenerative cohorts based on hyperglycemia reduction, and subsequently compared for differential production of mRNA and secreted proteins. Regenerative MSCs showed increased expression of matrix metalloproteases, epidermal growth factor receptor (EGFR)-activating ligands, and downstream effectors of Wnt signaling. Regenerative MSC supernatant also contained increased levels of pro-angiogenic versus pro-inflammatory cytokines, and augmented the expansion of ductal epithelial but not beta cells in vitro. Conversely, co-culture with UCB ALDH(hi) cells induced beta cell but not ductal epithelial cell proliferation. Sequential transplantation of MSCs followed by UCB ALDH(hi) cells improved hyperglycemia and glucose tolerance by increasing beta cell mass associated with the ductal epithelium and by augmenting intra-islet capillary densities. Thus, combinatorial human progenitor cell transplantation stimulated both islet-regenerative and revascularization programs. Understanding the progenitor-specific pathways that modulate islet-regenerative and revascularization processes may provide new approaches for diabetes therapy.

Umbilical Cord Blood‐Derived Aldehyde Dehydrogenase‐Expressing Progenitor Cells Promote Recovery from Acute Ischemic Injury

“…Although the engraftment of human cells within ischemic muscle was infrequent, UCB ALDH hi cells were specifically recruited to the ischemic limb within 3 days of transplantation and stimulated the recovery of blood vessel and capillary density. Furthermore, ALDH hi cells function within the pancreas to promote islet revascularization after transplantation into streptozotocin-treated mice [45,46]. Collectively, these data suggest that UCB ALDH hi progenitor cells represent a readily available population of proangiogenic cells for the development of cellular therapies to promote endogenous revascularization.…”

Proteomic characterisation reveals active Wnt-signalling by human multipotent stromal cells as a key regulator of beta cell survival and proliferation

“…There was a significant reduction in blood glucose AUC for MSC R vs MSC NR samples (Fig. 1b) [14,15]. Cell surface phenotype showed that both MSC R and MSC NR expressed the stromal markers CD90 and CD105 (>95%) without expression of the pan-leucocyte marker CD45 (data not shown).…”

“…In contrast, transplanted MSCs initiated endogenous islet recovery via paracrine stimulation [13]. In a series of publications, we have shown that human BM-derived MSCs stimulated the emergence of small, recipient-derived islet-like structures associated with the ductal epithelial niche within 7 days of injection into streptozotocin (STZ)-treated hyperglycaemic NOD/SCID mice [14,15]. Unfortunately, MSC samples showed donordependent variability in the capacity to improve glycaemia and prolonged expansion ex vivo reduced islet regenerative prowess [14].…”

Preliminary evaluation of intravenous infusion and intrapancreatic injection of human umbilical cord blood-derived mesenchymal stem cells for the treatment of diabetic mice

“…This research group also showed that, at only 14 days after MSC transplantation, the blood glucose level decreased to lower than 200 mg/dl; and, after 28 days, it was reduced to that of normal mice (< 126 mg/dl). The transplantation of MSCs also simultaneously increased the number of IPCs and the insulin level in the blood (Bell et al, 2012).…”

“…This positive paracrine effect on the damaged beta cells could help to protect these cells from apoptosis and to promote the proliferation of intrinsic pancreatic progenitor cells. This effect is also related to angiogenesis, cell protection, anti-inflammatory activities, promotion of mitosis, and apoptosis resistance (Bell et al, 2012;Gao et al, 2014;Xu et al, 2008). Furthermore, MSCs can trans-differentiate into insulin-producing cells (IPCs) in vivo in a suitable microenvironment (Chang et al, 2007).…”