Deng Hongkui's research group established a new islet transplantation strategy to solve the key problems of stem cell treatment for diabetes

On January 9, 2023, Deng Hongkui's research group from the School of Basic Medical Sciences of Peking University Health Science Center and Peng Xiaozhong's research group from the Chinese Academy of Medical Sciences/Peking Union Medical College collaborated on Nature Metabolism Published a research paper
entitled Implantation underneath the abdominal anterior rectus sheath enables effective and functional engraftment of stem cell-derived islets.
This study has developed a novel islet transplantation strategy to effectively support the survival, functional maturation and long-term maintenance of islet cells differentiated from human pluripotent stem cells in vivo
.
Compared with the traditional islet transplantation strategy, this scheme is less invasive, easy to operate, and easy to track and observe the graft for a long time.
More importantly, islet cells derived from pluripotent stem cells were transplanted into vivo using this protocol, and the cell function was significantly better than that commonly used in clinical practice
.

Diabetes is a major disease
that threatens human health.
Due to the difficulty of achieving precise regulation of blood sugar, the current commonly used treatment methods lead to a variety of complications, seriously affecting the quality of life of patients, and even endangering life
.
For patients with insulin-dependent diabetes, islet transplantation can completely free the patient from insulin injection, achieve disease cure, and is an ideal way
to treat diabetes in the future.
However, islet transplantation-dependent human islet tissue donors are extremely scarce, making this treatment strategy difficult to be widely used
.
Human pluripotent stem cells have the potential to proliferate and differentiate into islet cells indefinitely, which is expected to become a new solution
to the problem of diabetes cure.

The use of human pluripotent stem cells to treat type 1 diabetes requires solving three key problems: how to obtain human pluripotent stem cells, how to induce the differentiation of human pluripotent stem cells into islet cells, and how to transplant islet cells into the body
.
In 2022, Deng Hongkui's research group established a safe, simple, easy-to-regulate and standardized human pluripotent stem cell preparation technology, namely chemical reprogramming technology, which completely uses small molecules to induce the transformation of human adult cells into pluripotent stem cells (hCiPSCs) (Nature, 2022).

。 Deng Hongkui's research group further induces differentiated islet cells (hCiPSC-islets) in the direction of hCiPSCs and demonstrates the safety and efficacy of hCiPSC-islets in the treatment of type 1 diabetes in non-human primate models (Nature Medicine, 2022).

。 After solving the two problems of human pluripotent stem cell source and directional differentiation, the key bottleneck is how to efficiently transplant the islet cells differentiated from pluripotent stem cells back into the body and function for a long time
.

The commonly used strategy of islet cell transplantation is hepatic portal vein transplantation, and the islets are colonized in the
liver for a long time after transplantation.
In 2000, the Shapiro team at the University of Alberta in Canada established the Edmonton protocol, which enabled patients with type 1 diabetes who received islet transplantation to completely get rid of exogenous insulin injection, return blood sugar to normal levels, and achieve a cure
of the disease.
However, liver intraportal transplantation carries a higher risk of bleeding and clotting; More seriously, an immediate inflammatory reaction occurs in the early stages of islet transplantation, resulting in the mass death
of islet cells.
At the same time, the transplanted islets are diffused in the liver, which is difficult to track and cannot be removed
.
These safety and efficacy concerns make islet transplantation urgently require a more ideal transplant regimen
.

Fig.
1 Schematic diagram of subsheath transplantation of rectus abdominis muscle of islet cells differentiated from human pluripotent stem cells
.

The development of a transplantation scheme with high cell survival rate, good safety, and functional maturation and long-term maintenance of islet cells conducive to the differentiation of human pluripotent stem cells is a scientific problem
that urgently needs to be solved in the clinical transformation of islets differentiated by human pluripotent stem cells.
In this study, the researchers established a completely new transplantation strategy: anterior subthecal transplantation
of the rectus abdominis muscle.
Compared with portal venous transplantation, rectus abdominis anterior subthecal transplantation has obvious
advantages.
First of all, the surgical plan is safe and easy, and the transplantation can be completed under the guidance of B-ultrasound, and there is no risk
of bleeding and coagulation during the transplantation process.
Second, the graft is confined to a specific space under the anterior sheath of the rectus abdominis muscle, and the graft can be monitored and controlled by imaging (Figure 1).

Compared with other extraperitoneal transplantation protocols (subcutaneous and intramuscular transplantation), rectus abdominis transplantation is effective in supporting early cell survival and long-term function maintenance of human pluripotent stem cell (hCiPSC)-differentiated islet cells (Figure 2).

Figure 2 Comparison of three migration strategies

The investigators infused hCiPSC-islets under the anterior sheath of the rectus abdominis muscle in diabetic model monkeys, and blood glucose control was significantly improved in all diabetic monkeys transplanted (Figure 3).

From 6 weeks after transplantation, fasting blood glucose, preprandial blood glucose, and blood glucose 2 hours after prandial decreased to less than
10 mM.
At 12 weeks post-transplantation, glycated hemoglobin (HbA1c) decreased by an average of 44%, reaching healthy monkey levels; At the same time, exogenous insulin infusion decreased by 43%.

Fig.
3 After hCiPSC-differentiated islet cells were implanted into the anterior sheath of the rectus abdominis muscle, blood glucose control was significantly improved
in diabetic monkeys.

The researchers also confirmed that after hCiPSC-islets transplantation, endogenous insulin secretion levels were greatly increased and could respond to changes in blood glucose concentration; Compared with liver portal vein transplantation, the secretion level of insulin marker (C-peptide) in the new transplantation regimen increased by more than 5 times, and the C-peptide secretion level in one diabetic monkey reached the level of
healthy people.
This result shows that in the future clinical transplantation of human pluripotent stem cell differentiated islet cells, subsheath transplantation of rectus abdominis is expected to completely free diabetic patients from insulin injection and achieve a cure
of type 1 diabetes.

In summary, this study proves that rectus abdominis anterior subthecal transplantation is a novel transplantation strategy
suitable for the transplantation of human pluripotent stem cell differentiated islets.
Its operation method is simple, there are few transplantation-related adverse reactions, and the pluripotent stem cell differentiated islet cells survive efficiently, gradually obtain mature functions in the body and maintain their physiological functions
stably for a long time.
These advantages make rectus abdominis subthecal transplantation an ideal transplantation strategy
for future human pluripotent stem cells for clinical diabetes treatment.
This transplant strategy may also be widely used for many other types of cells
.

Nature Metabolism's research briefing, meanwhile, commented: "The results are exciting
.
First, the study provides a completely new site for islet cell transplantation, which is convenient for transplantation and has a large
cell volume.
Second, the transplanted islet cells survive and function well
at the site.
In addition, from a clinical translational point of view, it is significant that the study is implemented on non-human primate models"
.
Professor Gordon Weir, one of the reviewers and an internationally renowned expert in the field of diabetes research, spoke highly of the study: "This study strongly demonstrates the potential value
of subsheath of the rectus abdominis as a transplant site for islet cells that induce pluripotent stem cell (iPS) differentiation.
This transplant site may be extended to any source of cell transplantation
.
The survival and function of transplanted tissue at this site is impressive
.
”

Professor Deng Hongkui and Dr.
Du Yuanyuan of the School of Basic Medical Sciences, Peking University Health Science Center, and Professor Peng Xiaozhong of the Chinese Academy of Medical Sciences/Peking Union Medical College are the co-corresponding authors
of the paper.
Dr.
Liang Zhen, Dr.
Sun Dong and Dr.
Lu Shuaiyao are co-first authors
of this paper.
Professor Lou Jinning, Professor Weiguo and Professor Luo Zhifeng of the Affiliated Hospital of Guilin University, Professor Shen Zhongyang and Professor Wang Shusen of Tianjin First Central Hospital made important contributions
to this paper.
This research was supported by the National Natural Science Foundation of China, the Peking University-Tsinghua Joint Center for Life Sciences, and the Zhejiang Lingyan Program.

Original text:

(School of Basic Medicine, Peking University)