Challenges associated with regenerative therapy/ cell replacement therapy in Diabetes

The current International Diabetes Federation (IDF) atlas indicate that every one in eleven (slowly approaching one in ten) adults are suffering from Diabetes. The true number is more alarming as a significant percentage of diabetic patients go undiagnosed. The main issue in diabetes is the dwindling beta cell population within the endocrine pancreas (islets), which significantly limits the biosynthesis and secretion of insulin.

Scientists have been trying to come around this problem by exploring various means to generate new functional islets as there is a heavy limitation on donor (cadaveric) islets and all the other therapeutic drugs currently available in the market can only manage the diabetic condition, which is far from a cure.

It is not that its impossible to replace the islets but there are a plethora of real time challenges involved in this process. I just wanted to take this opportunity and open a discussion that may help us understand these challenges more vividly.

• Differentiation process for various stem cell population for generating islet clusters is different: The advent of stem cell technology has allowed us to reprogram various stem cells for generating islets. However, with various stem cells sources the process or the in-between steps involved to generate functional islets vary significantly e.g. Embryonic stem cells or iPSCs which haven't entered any of the dermal lineages are completely naive cells. Hence, they first need to be brought in the endodermal lineage, followed by pancreatic, endocrine pancreatic and then specialize into insulin producing islets or more specifically beta cells. However, this take anywhere between 30 to 45 days, which is even longer for iPSCs if we include the time to generate iPSCs. Another limitation of this is low expression of certain transcription factors essential to maintain islet homeostasis, which does not allow the differentiated islets to function optimally. If we talk about adult stem cells like mesenchymal stem cells from bone marrow or adipose tissue, the time taken is significantly reduced however, the protocols available do not focus on optimizing the functionality or quality of the islets produced. Hence, there is a serious need for optimizing protocols in terms of both islet yield and quality. Further, among adult stem cells the easiest to differentiate into functional robust islets is pancreatic progenitors, which takes the shortest route in differentiation but there are clinical limitations on their isolation from healthy donors. Therefore, triggering resident endocrine progenitors within pancreas for replenishing lost beta cells is another pivotal research area that can change the dynamics of diabetes therapeutics. There are also groups who have been targeting acinar and alpha cells within the islets to replace beta cells population. 
• Responsiveness to glucose varies with different sources used for generating islet clusters: Glucose sensing and releasing endocrine hormones like insulin and glucagon in response to blood glucose levels for regulating glucose homeostasis is the essence of functional islets. However, the quality of islet vary with different stem cell sources and different protocols, which generates islets with varying responsiveness to glucose.     
  
• Cell death and islet longevity is a challenge: Islets being an agglomeration of tightly packed cells is prone to cellular damage. Central necrosis in islets is very common owing to lack of nourishment towards the inner most regions of the islets. It is very difficult to maintain islets in culture for more than a week, after which they began to display signs of senescence. Further, currently there is no effective method by which islets could be cryo-preserved for long periods of time without compromising their quality. Its speculated that modified vitrification methods could be one of the ways to achieve prolonged islet preservation but it needs to be clinically substantiated.
  
• Functionality of islets greatly reflect its composition and architecture, controlling which is again a challenge: I personally believe that islet architecture could be the key to decipher and gain robust control on cellular fate and function within islets. The cellular arrangement in human islet even though seems random but is in a profound stochastic state. Mapping the orientation and sequencing analysis of cells within islets could help us identify the spacial configuration of endocrine cells within the islets. 

 I will be expanding more on islet architecture in another article. Hence, lets end this here. If the readers think there are other limitations that I have not included, please feel free to comment and suggest. Thank you for taking out some time for reading this. You are awesome!!!