Adipose cells are plentiful source of stem cells for use in spinal fusion surgeries


Adipose cells, better known as fat, may be the least popular component of the human body. However, most people don’t realize that fat actually has many important functions in establishing and maintaining good health – providing energy, insulating the body against heat loss and protecting nerves, just to name a few.

Now, researchers at Johns Hopkins Medicine suggest there’s another role for the poor maligned adipose cell: a practical and plentiful source of stem cells for use in spinal fusion surgeries.

Spinal fusion, used to correct problems in the spine, is the “welding” together of two or more vertebrae so that they heal into a single, solid bone.

Unfortunately, the surgery – using bone taken from other parts of the patient’s body – fails in up to one out of every five procedures. Researchers have found that stem cells, harvested from a patient’s marrow and allowed to mature into bone cells, can yield successful outcomes when used in spinal fusions.

However, the aspiration method for extracting stem cells from the marrow carries a risk of infection and often is painful.

In a study published in the May 2021 issue of the journal Spine, Timothy Witham, M.D., director of the Johns Hopkins Neurosurgery Spinal Fusion Laboratory, Alexander Perdomo-Pantoja, M.D., a postdoctoral fellow at the Johns Hopkins University School of Medicine, and Christina Holmes, Ph.D., a former Johns Hopkins Medicine postdoctoral fellow now at Florida State University, worked together with colleagues to try out adipose cells rather than bone marrow as a source for the stem cells.

Performing spinal fusion procedures in rats, the researchers found that freshly isolated stem cells from fat worked just as well as the more commonly used bone marrow stem cells. The researchers say this suggests the technique could be a candidate for human clinical trials.

“Bone marrow stem cells are isolated in human patients from the hip,” says Holmes. “But using a huge needle to take out bone marrow is a painful procedure, and we can only get a limited number of cells, so we’ve found an alternative source by using stem cells from fat.”

Perdomo-Pantoja says spinal fusion procedures are used to treat many different conditions.

“Spinal fusions are used for anything that causes spinal instability, which usually produces significant mechanical pain,” he says. “You see it frequently when we get older as the intervertebral discs, ligaments and muscles in the spine deteriorate. But these procedures can also be used to treat instability when it is caused by tumors, fractures, deformities or trauma.”

In this study, Witham, Perdomo-Pantoja, Holmes and their team isolated stem cells from fat and bone marrow, and then implanted them into rat spines. For the adipose-derived stem cells, the researchers chose to use freshly isolated cells to see if they could make the procedure simpler and faster.

Currently, stem cells from either bone marrow or fat are frequently grown in a laboratory culture to get them mature enough for a spinal fusion. During culturing, there is some risk of contamination or transformation into unusable bone. Holmes says that freshly isolating cells avoids these problems, along with being less labor intensive and cheaper because expensive processing materials are not needed.

While stem cells from fat are commonly used in cosmetic procedures, they are not often used in spinal fusions, she adds.

“We feel that fat cells are a logical alternative to bone marrow cells because most patients have an adequate supply of fat cells,” Witham says.

Fat also is much more accessible during surgery and can be harvested with less stem cell death than bone marrow.

Spinal fusion is a very common procedure, and we feel this approach could be applied across a wide cohort of spinal fusion patients.”

The researchers also were pleased to see the quality of the bone created by both forms of stem cells. They found significantly more bone formation and blood supply in the fresh adipose-derived stem cells compared with what they observed in previous studies with cultured cells from both fat and bone marrow.

Witham and his team hope to further their research by next identifying which cells are the most advantageous for spinal fusions and then characterizing them.

The defining characteristics of mesenchymal stem cells (MSCs) are their capacity to self-renew and their multipotency to differentiate into more than one cell type and remain in this state for long periods [1]. Furthermore, MSCs produce growth factors and cytokines that are involved in immunomodulation and regeneration. This immunomodulatory capacity of MSCs enables them to be used in cell therapies, especially in autoimmune diseases, host grafting and organ transplantation [2]. In addition, tissue-derived stem cells have a degree of plasticity, depending on their type. This manifests in the differentiation phenotypic potential that goes beyond the cell phenotype of their original tissue [3].

Mesenchymal stem cells have been isolated from several different tissues [4,5] using a variety of different methods, although the most accessible site is adipose tissue [6]. Adipose tissue has a significantly higher concentration of MSCs than bone marrow (1% versus > 0.01%) and other sources, including the dermis, the umbilical cord, dental pulp and the placenta [7].

Moreover, harvesting from adipose tissue is less invasive when compared to the bone marrow, resulting in less risk of severe complications and no ethical limitations [6]. It was established that the positive expression of surface markers CD13, CD29, CD44, CD73, CD90 and CD105, and negative or low production of HLA-DR characterizes MSCs [8,9]. Adipose tissue (AT)-derived MSCs tend to be more heterogeneous [10] and exhibit immunomodulatory characteristics, in addition to their differentiation ability similar to bone marrow-derived MSCs (BM-MSCs) [11].

To prevent the incorrect use of different and diverse terminology, the International Fat Applied Technology Society adopted the term “adipose-derived stem cells” (ASCs) to identify the isolated, plastic-adherent and multipotent cell population obtained from this site (Figure 1) [12].

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Figure 1
Morphology of ASCs. (A) Isolated ASCs are typically expanded in monolayer (2D) culture plastic (original 20× magnification) and (B) ASCs colony-forming potential (original 4× magnification).

Adipose tissue is a complex connective tissue that originated from the mesodermal: an energy homeostasis regulator, which exhibits morphologic, functional and regulatory heterogeneity [13]. Several types of cells compose AT, including preadipocytes, mature adipocytes, vascular smooth muscle cells, fibroblasts, resident monocytes, endothelial cells, macrophages and lymphocytes [14]. The immune, endocrine, reproductive, and hematopoietic systems are influenced by AT, acting in the inflammatory response and many other functions [15].

Understanding the heterogeneity of ASCs and how to optimize their properties, can contribute to making the best clinical use of them and lead to more effective tissue engineering.

Cellular Heterogeneity

Adipose-derived stem cells are a potent cell population. They are influenced by environment and genetic composition and display differences to their niche in the body, as well as proliferation capacity and stemness [26]. Furthermore, the same AT isolation site may contain several types of ASCs, and as it is a rich cell niche, each cell may lead to a different possible therapeutic application [27].

The exact site of ASCs into adipose tissue has not been well defined, and therefore, the composition of the adipose tissue depends on each individual group. One of the reasons is the high tissue vascularization and the presence of the various cell types [27].

It is known, nonetheless, that AT includes endothelial cells, immune cells, pericytes, fibroblasts, vascular cells, preadipocytes ASCs and hematopoietic stem cells. Stem Cell and progenitor cells resolve about 3% of all cell populations [28]. The process of adipogenesis and angiogenesis can be closely related, moreover pericytes exhibit multipotency similar to that of stem cells [29,30]. Importantly, these stromal and immune cell types play critical roles in the establishment and maintenance of parenchymal cell function. The composition of stromal cells varies across fat depots, reflecting tissue specialization and differences in energy storage, vascularization, innervation and metabolism [31,32].

Owing to its essential role in metabolism, there is considerable interest in better defining cellular subtypes involved in AT homeostasis and the mechanisms that regulate in vivo adipogenesis, plasticity and inflammatory processes for targeted therapeutic strategies to treat metabolic and autoimmune disease [20].

Adipose-Derived Stem Cell

Correlated with BM-MSCs, ASCs exhibit a greater proliferative capacity and present telomerase activity. Even though this activity is lower than the one observed in tumor cell lines, it confirms the ASCs self-renewal and proliferation ability [33]. Adipose-derived stem cells advocate tissue regeneration and repair by secreting growth factors, cytokines, angiogenic factors, adipokines and neurotrophic factors that stimulate restoration of normal tissue function or reduce the damage [26].

Molecules released by ASCs play essential roles in the vitality of other cells and mechanisms associated with central nervous system, immune system, heart and muscles [34]. The cytokine profile of ASCS comprises, pro/anti-inflammatory, angiogenic and hematopoietic factors, being interleukins (IL-6, IL-7, IL-10, IL-11), vascular endothelial growth factor (VEGF), basic fibroblastic growth factor (bFGF), tumor necrosis factor-alpha (TNF-α), granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF) [35]. The immunosuppressive properties of ASCs can result from the release of Indoleamine-2,3-dioxygenase and prostaglandin E2 [36,37].

Through the secretion of brain-derived neurotrophic factor, glial-derived neurotrophic factor, nerve growth factor and insulin-like growth factor (IGF) [34], ASCs show neuroprotective action and promote the regeneration of central nervous system tissues.

Adipose-derived stem cells are also immune-privileged due to the negative or low expression of human leukocyte antigen (HLA) expression and inhibition of proliferation of activated allogeneic lymphocytes [38,39]. These cells exert protector effects against organ rejection and avoid graft versus host disease after allogeneic transplantation.

The immunophenotype of ASCs can express other essential factors involved in stemness, self-renewal and differentiation potentials, such as CD146 and CD271. They are also related to enhanced capacity for healing bone defects or cartilage or to differential paracrine wound healing activity [40,41].

Li and collaborators isolated a CD146+ subpopulation from ASCs and tested for cartilage regeneration [40]. Cartilage lesions typically result in inflammation and represent an important test in cartilage repair [42]. The inflammation-modulating property in the animal model reported better results during the early stage of intra-articular injections of CD146+ ASCs.

In another study, Kohli and collaborators showed that derived CD271+ ASCs were demonstrated to be macroscopically superior for promoting cartilage repair of osteochondral tissue damage when compared with defects received transplants of plastic adherent ASCs and the control group of scaffold alone [41]. Imperatively, in animal cell transplantation groups, there was slight evidence of mature hyaline cartilage or new bone tissue.

These studies emphasized the importance of discovering the functional features of specific subtypes of ASCs, to be used as a new path for cell-based tissue engineering research.

reference link:

More information: Alexander Perdomo-Pantoja et al. Comparison of Freshly Isolated Adipose Tissue-derived Stromal Vascular Fraction and Bone Marrow Cells in a Posterolateral Lumbar Spinal Fusion Model, Spine (2020). DOI: 10.1097/BRS.0000000000003709


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