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Patil, S. Glucose and Serum Deprivation in Stem Cells. Encyclopedia. Available online: https://encyclopedia.pub/entry/17972 (accessed on 13 December 2025).
Patil S. Glucose and Serum Deprivation in Stem Cells. Encyclopedia. Available at: https://encyclopedia.pub/entry/17972. Accessed December 13, 2025.
Patil, Shankargouda. "Glucose and Serum Deprivation in Stem Cells" Encyclopedia, https://encyclopedia.pub/entry/17972 (accessed December 13, 2025).
Patil, S. (2022, January 10). Glucose and Serum Deprivation in Stem Cells. In Encyclopedia. https://encyclopedia.pub/entry/17972
Patil, Shankargouda. "Glucose and Serum Deprivation in Stem Cells." Encyclopedia. Web. 10 January, 2022.
Glucose and Serum Deprivation in Stem Cells
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This entry is adapted from the peer-reviewed paper 10.3390/jpm12010018

Stem cell therapy is an evolving treatment strategy in regenerative medicine. Recent studies report stem cells from human exfoliated deciduous teeth could complement the traditional mesenchymal stem cell sources. Stem cells from human exfoliated deciduous teeth exhibit mesenchymal characteristics with multilineage differentiation potential. Mesenchymal stem cells are widely investigated for cell therapy and disease modeling.

nutrient deprivation SHEDs AMPK stemness

1. Introduction

Stem cell therapy is one of the promising clinical approaches which will be a game changer for treating many diseases. However, there are so many challenges for the translating the technique from bench to bed side. Genetic instability of stem cells, immunological rejection by host immune system, stem cell culturing conditions, pharmacokinetic behavior of stem cells and ethical issues are some of the challenges in stem cell therapy [1]. Postnatal isolation of stem cells can be carried out from various tissues such as hair follicles, bone marrow, muscles and dental pulp [2][3][4]. Recently, Miura et al., showed human deciduous tooth as a source of multipotent stem cells and these stem cells from human exfoliated deciduous teeth (SHEDs) exhibited mesenchymal characteristics [5]. SHEDs are isolated from the dental pulp of physiologically shed deciduous tooth. 
The proliferation and multipotential differentiation capacity of SHEDs have been shown in in-vitro and in-vivo models. SHEDs can differentiate into multiple lineages such as adipocytes, osteoblasts, endothelial cells, and neuronal-like cells [6][7]. The potential of SHEDs in repairing damaged tooth, induction of bone regeneration and to treat neural tissue injuries as well as degenerative diseases are under study [8]. It has been reported that SHEDs have higher proliferative aptitude than bone marrow derived mesenchymal stromal cells. SHEDs also possess high osteogenic differentiation potential than the stem cells from human dental pulp [9]. Gene expression profile of SHEDs showed high expression of genes associated with high proliferation [9]. Mesenchymal characteristics of SHEDs were also investigated and proposed SHEDs as an alternative source of Mesenchymal stem cells (MSCs). MSCs are multipotent stem cells which can be for tissue repair and for many clinical applications including cancer treatment. The Currently, several clinical trials have been carried out for demonstrating the efficacy of MSC in clinical application [10].
There are many factors which affect the differentiation potential of the MSC. Heterogeneity of MSCs, variation in expansion capacity of MSCs due to different culture conditions, immune status of the recipient is some of them [11]. The microenvironment of MSCs affect the differentiation fate of MSCs [11]. Additionally, MSCs are highly glycolytic and glucose deprivation and nutrient supply due to damaged blood vessels during tissue regeneration is one of the major challenges [12][13]. Therefore, understanding the effect of low glucose and nutrients on MSCs will be immensely useful. It has been reported that MSCs, increased reactive oxygen species (ROS) can reduce the proliferative potential, increase senescence, enhance adipogenic but reduce osteogenic differentiation [6]. A study conducted on human bone marrow-derived MSCs showed that serum mediated oxidative stress can affect the function of the mesenchymal cells [7]. Serum deprivation has many effects in cells, for example in Balb/c 3T3 fibroblasts cells serum deprivation led to induction of apoptosis [14]. However, the effect of serum deprivation and low glucose on SHEDs is not yet explored.

2. SHEDs Show MSC-like Morphology, Cell Surface Marker Expression, and Trilineage Differentiation

The SHEDs derived using the explant culture method is further characterized for the stemness as well as mesenchymal properties. The morphological analysis of SHEDs showed MSC-like characters under microscope (Figure 1A), positive marker expression of MSC-specific cell surface markers. The expression of MSC markers such as CD73, CD90, and CD105 were analyzed, and it is found that these cells presented positive marker expression for the MSC markers (Figure 1B–E), whereas non-MSC markers CD34, CD45 and MHC Class II antigen and HLA-DR showed negligible marker expression in SHEDs (Figure 1F–H). Furthermore, the differentiation potential of the derived SHEDs was checked . It can be observed that SHEDs successfully differentiated into adipocytes, chondrocytes, and osteoblasts, which validates the effective isolation of SHEDs (Figure 1I–K).
Jpm 12 00018 g001 550
Figure 1. Isolation, characterization flow cytometry for MSCs associated cell surface markers, and tri-lineage differentiation of SHEDs. (A) Photomicrograph of passage 2 SHEDs. Scale bar = 100 μm. (B–H) Characterization of SHEDs for MSC-specific positive cell surface markers CD73, CD90, CD105 and negative markers CD34, CD45, CD105. (I–K) Differentiation of SHEDs into osteoblasts, adipogenic lineage, and chondrogenic lineage. Scale bar = 100 µm. SHEDs: Stem cells from exfoliated deciduous tooth, Osteo: Osteogenic induction, Adipo: Adipogenic induction, Chondro: Chondrogenic induction.

3. Research Findings

In regenerative medicine, cell therapy is regarded as a promising strategy to treat the diseases which are caused by cell death. In recent years, the development of treatment methods has been a great hope. However, currently, there are many challenges for implementing stem cell-based therapy widely. One of the most important challenge is the complete functioning and fate of stem cells in the transplanted system. There are many factors which determine the fate of stem cells and the prime important one is the microenvironment. Recently it has been shown that, the tissue microenvironment can determine the proliferation, cell survival, and even de-differentiation of transplanted stem cells [15].

Mesenchymal stem cells (MSCs)due to their ability to differentiate into cells of different mesenchymal origin, it is widely under investigation in cell therapy. SHEDs obtained from the pulp of human deciduous pulp open a new avenue, due to the effortlessness of getting the samples and less ethical issues. The multilineage differentiation potential and proliferation potential of SHEDs compared to bone marrow MSCs suggests SHEDs can complement bone marrow MSCs [16]. The success of MSC based cell therapy primarily depends on factors such as status of host immune status, the microenvironment. The microenvironment factors such as inflammation, hypoxia, and extracellular matrix influence the homing and fate of transplanted MSCs [11]. 

The isolation of the SHEDs was carried out from the human deciduous teeth pulp and characterized. The morphological as well as cell surface marker-based characterization of SHEDs revealed mesenchymal property with a potential to differentiate into adipogenic, osteogenic and chondrogenic cell lineages. The incubation of SHEDs in nutrient deprived and low glucose medium leads to change in morphology of the cells. Although, phenotypically the cells were not showing mesenchymal morphology these cells showed, low expression of epithelial marker CD29, high expression of mesenchymal markers CD271 and pluripotent stem cell marker CD140b. These indicates the changes in cell morphology may be an adaptation to survive the low nutrient medium. Changes in cell morphology associated with low nutrients is previously reported in primary microglia and BV-2 cells [17]. CD140b is also an angiogenic mediator which might be activated due to the low glucose level [18]. It has been shown hypoxia and serum deprivation can induce angiogenesis [19]. Serum deprivation and low glucose level also reduced the differentiation potential of MSCs to osteogenic lineage. 

The results suggests that nutrient deprivation leads to the cell cycle arrest in S-phase via high expression of cyclin inhibitors, low expression of cyclin along with the elevated expression of transcription factor FOXO3. FOXO3 expression is directly regulated by the nutrient sensor AMP-activated protein kinase (AMPK) [20]. 

AMP-activated protein kinase (AMPK) plays an important role in maintaining homeostasis of energy, controls the metabolic pathways and also nutrient supply. AMPK is often known as cellular energy sensor as it can be activated by various conditions such as decrease in cellular energy levels, low glucose level, hypoxia and exposure to toxins [21]. AMPK primarily controls the balance of ATP and inhibits the anabolic pathways [22]. AMPK also regulates transcription of several metabolomic kinases. Recent studies showed the involvement of AMPK in cell polarity and cytoskeletal dynamics [23].

The research also showed that nutrient deprivation of SHEDs led to reduced proliferation, increased apoptosis, activation of stress sensing molecule AMPK and induced distinct differentiation lineages in SHEDs.

References

  1. Sah, J.P. Challenges of Stem Cell Therapy in Developing Country. J. Stem Cell Res. Ther. 2016, 1, 96–98.
  2. Prockop, D.J. Marrow Stromal Cells as Stem Cells for Nonhematopoietic Tissues. Science 1997, 276, 71–74.
  3. Weissman, I.L. Translating Stem and Progenitor Cell Biology to the Clinic: Barriers and Opportunities. Science 2000, 287, 1442–1446.
  4. Pittenger, M.F.; Mackay, A.M.; Beck, S.C.; Jaiswal, R.K.; Douglas, R.; Mosca, J.D.; Moorman, M.A.; Simonetti, D.W.; Craig, S.; Marshak, D.R. Multilineage Potential of Adult Human Mesenchymal Stem Cells. Science 1999, 284, 143–147.
  5. Govitvattana, N.; Osathanon, T.; Taebunpakul, S.; Pavasant, P. IL-6 regulated stress-induced Rex-1 expression in stem cells from human exfoliated deciduous teeth. Oral Dis. 2012, 19, 673–682.
  6. Denu, R.A.; Hematti, P. Effects of Oxidative Stress on Mesenchymal Stem Cell Biology. Oxidative Med. Cell. Longev. 2016, 2016, 2989076.
  7. Fonteneau, G.; Bony, C.; Goulabchand, R.; Maria, A.T.J.; Le Quellec, A.; Rivière, S.; Jorgensen, C.; Guilpain, P.; Noël, D. Serum-Mediated Oxidative Stress from Systemic Sclerosis Patients Affects Mesenchymal Stem Cell Function. Front. Immunol. 2017, 8, 988.
  8. Anoop, M.; Datta, I. Stem Cells Derived from Human Exfoliated Deciduous Teeth (SHED) in Neuronal Disorders: A Review. Curr. Stem Cell Res. Ther. 2021, 16, 535–550.
  9. Nakamura, S.; Yamada, Y.; Katagiri, W.; Sugito, T.; Ito, K.; Ueda, M. Stem Cell Proliferation Pathways Comparison between Human Exfoliated Deciduous Teeth and Dental Pulp Stem Cells by Gene Expression Profile from Promising Dental Pulp. J. Endod. 2009, 35, 1536–1542.
  10. Wang, S.; Qu, X.; Zhao, R.C. Clinical applications of mesenchymal stem cells. J. Hematol. Oncol. 2012, 5, 19.
  11. Zhou, T.; Yuan, Z.; Weng, J.; Pei, D.; Du, X.; He, C.; Lai, P. Challenges and advances in clinical applications of mesenchymal stromal cells. J. Hematol. Oncol. 2021, 14, 24.
  12. Nuschke, A.; Rodrigues, M.; Stolz, D.B.; Chu, C.T.; Griffith, L.; Wells, A. Human mesenchymal stem cells/multipotent stromal cells consume accumulated autophagosomes early in differentiation. Stem Cell Res. Ther. 2014, 5, 140.
  13. Farrell, M.; Shin, J.; Smith, L.; Mauck, R. Functional consequences of glucose and oxygen deprivation on engineered mesenchymal stem cell-based cartilage constructs. Osteoarthr. Cartil. 2015, 23, 134–142.
  14. Kulkarni, G.V.; A McCulloch, C. Serum deprivation induces apoptotic cell death in a subset of Balb/c 3T3 fibroblasts. J. Cell Sci. 1994, 107 Pt 5, 1169–1179.
  15. Wan, P.X.; Wang, B.W.; Wang, Z.C. Importance of the stem cell microenvironment for ophthalmological cell-based therapy. World J. Stem Cells 2015, 7, 448–460.
  16. Wang, H.; Zhong, Q.; Yang, T.; Qi, Y.; Fu, M.; Yang, X.; Qiao, L.; Ling, Q.; Liu, S.; Zhao, Y. Comparative characterization of SHED and DPSCs during extended cultivation in vitro. Mol. Med. Rep. 2018, 17, 6551–6559.
  17. Yao, Y.; Fu, K.Y. Serum-deprivation leads to activation-like changes in primary microglia and BV-2 cells but not astrocytes. Biomed. Rep. 2020, 13, 51.
  18. Periasamy, R.; Elshaer, S.L.; Gangaraju, R. CD140b (PDGFRbeta) signaling in adipose-derived stem cells mediates angiogenic behavior of retinal endothelial cells. Regen. Eng. Transl. Med. 2019, 5, 1–9.
  19. Luo, J.; Martinez, J.; Yin, X.; Sanchez, A.; Tripathy, D.; Grammas, P. Hypoxia induces angiogenic factors in brain microvascular endothelial cells. Microvasc. Res. 2012, 83, 138–145.
  20. Dávila, D.; Connolly, N.M.C.; Bonner, H.; Weisová, P.; Düssmann, H.; Concannon, C.G.; Huber, H.J.; Prehn, J.H.M. Two-step activation of FOXO3 by AMPK generates a coherent feed-forward loop determining excitotoxic cell fate. Cell Death Differ. 2012, 19, 1677–1688.
  21. Kim, J.; Yang, G.; Kim, Y.; Kim, J.; Ha, J. AMPK activators: mechanisms of action and physiological activities. Exp. Mol. Med. 2016, 48, e224.
  22. Mihaylova, M.M.; Shaw, R.J. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat. Cell Biol. 2011, 13, 1016–1023.
  23. Mirouse, V.; Billaud, M. The LKB1/AMPK polarity pathway. FEBS Lett. 2010, 585, 981–985.
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Subjects: Agriculture, Dairy & Animal Science
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Update Date: 11 Jan 2022
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