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Reselected Hematopoietic Progenitors as a Treatment for Diabetes?

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Review of “Expanded Hematopoietic Progenitor Cells Re-Selected for High Aldehyde Dehydrogenase Activity Demonstrate Islet Regenerative Functions” from Stem Cells by Stuart P. Atkinson

While most cell-based treatments for diabetes aim to replace lost or dysfunctional pancreatic β cells (the cells which produce insulin), some studies have suggested that transplanted cells can also stimulate the regeneration of the β cell population, and in so much, represents an alternative strategy to treat diabetes.

Previous studies by David A. Hess established that bone marrow-derived hematopoietic progenitors cells (HPCs) can reduce hyperglycemia in a mouse model of β cell deletion [1]. However, the detrimental effects of diabetes on progenitor function [2] unfortunately complicates autologous therapies such as this.

In an attempt to side-step this problem, their new study assessed the potential of human HLA-phenotyped umbilical cord blood (UCB) samples as an allogeneic healthy source of HPCs [3]. Via reselecting cells with high aldehyde dehydrogenase (ALDH) activity, a cytosolic detoxification enzyme highly expressed in progenitors [4], the authors now show that reselected UCB-HPCs may represent an improved therapeutic option.

Initial serum-free and xeno-free culture amplification of small amounts (4 × 10 5) of UCB ALDHhi cells, representing primitive hematopoietic/early myeloid progenitors, met with early success. However, the proportion of ALDHhi cells diminished significantly with time in culture, and so, to avoid this problem, the authors reselected ALDHhi cells before this occurred. These amplified and reselected cells retained the expression of primitive hematopoietic cell surface markers (CD34 and CD133), displayed high levels of hematopoietic colony forming cell function in vitro, and expressed a gene expression profile associated with matrix reorganization and proangiogenic processes.

The reselection process, therefore, allowed the amplification of those cells which retain their HPC characteristics, but will their functionality remain in vivo? To answer this question, the authors transplanted various populations of cells into a mouse model of diabetes (STZ-treated NOD/SCID mice), finding that selected ALDHhi cells, but not unselected cells or ALDHlo cells, had the ability to reduce hyperglycemia. This ability to reduce blood sugar levels correlated to ALDHhi cell engraftment in the mouse bone marrow, but not engraftment into the mouse pancreas. However, transplantation of reselected ALDHhi cells did lead to a significant increase in islet circumference and total β cell mass, suggestive of direct stimulation of endogenous islet recovery. In support of recovery, the authors observed an increase in islet-associated β cell proliferation and also an increase in intra-islet microvessel density (CD31 expression) (See Figure). 

Previous studies by this group had suggested that ALDHhi cells form the UCB may be therapeutically relevant [5, 6] and, in this new study, they prove that expansion and reselection of these cells represents a practical means with which to produce the quantity of cells required for therapeutic application. Quite how these stem cells promote regeneration will require further assessment, but as we now have the means to amplify and assess large number of functional progenitor cells in vitro, this strategy could develop into an important approach to battle diabetes.

Discussion Points

  • Does this strategy represent a relevant treatment option for human patients?
  • Can reselection of other stem cells extend their therapeutic relevance?
  • Can we engineer reselected cells to improve migration and engraftment after transplantation?

References

  1. Hess D, Li L, Martin M, et al. Bone marrow-derived stem cells initiate pancreatic regeneration. Nat Biotechnol 2003;21:763-770.
  2. Hess DA and Hegele RA Linking diabetes with oxidative stress, adipokines, and impaired endothelial precursor cell function. Can J Cardiol 2012;28:629-630.
  3. Seneviratne AK, Bell GI, Sherman SE, et al. Expanded Hematopoietic Progenitor Cells Reselected for High Aldehyde Dehydrogenase Activity Demonstrate Islet Regenerative Functions. STEM CELLS 2016;34:873-887.
  4. Storms RW, Trujillo AP, Springer JB, et al. Isolation of primitive human hematopoietic progenitors on the basis of aldehyde dehydrogenase activity. Proc Natl Acad Sci U S A 1999;96:9118-9123.
  5. Bell GI, Meschino MT, Hughes-Large JM, et al. Combinatorial human progenitor cell transplantation optimizes islet regeneration through secretion of paracrine factors. Stem Cells Dev 2012;21:1863-1876.
  6. Bell GI, Putman DM, Hughes-Large JM, et al. Intrapancreatic delivery of human umbilical cord blood aldehyde dehydrogenase-producing cells promotes islet regeneration. Diabetologia 2012;55:1755-1760.